Antibodies

ABSTRACT

The invention relates to antibodies useful for the prevention, treatment and/or diagnosis of coronavirus infections, and diseases and/or complications associated with coronavirus infections, including COVID-19. In particular, the invention relates to antibodies capable of binding to the spike protein of coronavirus SARS-CoV-2 and uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to GB Application No. 2202232.1 (filedFeb. 18, 2022), GB Application No. 2203423.5 (filed Mar. 11, 2022), GBApplication No. 2206777.1 (filed May 9, 2022), GB Application No.2212470.5 (filed Aug. 26, 2022), GB Application No. 2214036.2 (filedSep. 26, 2022), GB Application No. 2215418.1 (filed Oct. 18, 2022), andGB Application No. 2301959.9 (filed Feb. 10, 2023), each of which isherein incorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The content of the electronically submitted sequence listing (Name:2943_2240005_Seqlisting_ST26; Size: 858,636 bytes; and Date of Creation:Feb. 17, 2023) filed with the application is incorporated herein byreference in its entirety.

FIELD OF INVENTION

The invention relates to antibodies useful for the prevention, treatmentand/or diagnosis of coronavirus infections, and diseases and/orcomplications associated with coronavirus infections, includingCOVID-19.

BACKGROUND OF THE INVENTION

A severe viral acute respiratory syndrome named COVID-19 was firstreported in Wuhan, China in December 2019. The virus rapidlydisseminated globally leading to the pandemic with >200M confirmedinfections and over 4.4M deaths in 12 months. The causative agent,SARS-CoV-2, is a beta coronavirus, related to SARS-CoV-1 and MERScoronaviruses, all of which cause severe respiratory syndromes.

Tremendous advances in our understanding of the disease and the virushave been made in the months since the identification of SARS-CoV-2 asthe causative agent a of COVID-19. There are now a number of proventreatments including dexamethasone and Tocilizumab as well as monoclonalantibodies (mAbs), which have been shown to be effective when used inboth prophylactic and therapeutic settings (Baum et al., 2020, Science369, 1014-1018). Despite these advances, the pandemic is far from undercontrol, leading to successive waves of infection.

Coronaviruses have four structural proteins: nucleocapsid, envelope,membrane and spike (S) proteins. The spike protein is the most prominentsurface protein. It has an elongated trimeric structure and isresponsible for engagement of target cells and triggering fusion ofviral and host membranes. The spike protein from SARS-CoV-2 andSARS-CoV-1 both use angiotensin-converting enzyme 2 (ACE2) as a cellsurface receptor. ACE2 is expressed in a number of tissues, includingepithelial cells of the upper and lower respiratory tracts.

The S protein consists of two subunits, S1, which mediates receptorbinding, and S2, responsible for viral and host cell membrane fusion. Itis a dynamic structure capable of transitioning to a post-fusion stateby cleavage between S1 and S2 following receptor binding or trypsintreatment. In some SARS-CoV-2 sequences a furin protease cleavage siteis inserted between the S1 and S2 subunits, and a mutation of thecleavage site attenuates disease in animal models. The S1 fragmentoccupies the membrane distal tip of S and can be subdivided into an Nterminal domain (NTD) and receptor binding domain (RBD). While bothregions are immunogenic, the RBD contains the interacting surface forACE2 binding. Although usually packed down against the top of S2, RBDscan swing upwards to engage ACE2. Monoclonal antibodies (mAbs) recognizeone or both of ‘up’ and ‘down’ conformations.

The S protein is relatively conserved between SARS-CoV-2 and SARS-CoV-1(76%), but the RBD and NTD are less conserved (74% and 50% respectively)than the S2 domain (90%). Conservation with MERS-CoV and the seasonalhuman coronaviruses is much lower (19-21%). Overall, SARS-CoV-2antibodies show limited cross-reactivity, even with SARS-CoV-1.

S is involved in viral attachment to target cells via the interaction ofcell surface expressed ACE2 with the S receptor binding motif (otherwiseknown as the ACE-2 footprint), a 25 amino acid patch that lies at thetip of the receptor binding domain (RBD), in the S1 fragment of spike.Following attachment, cleavage of S releases S1, allowing a majorconformational change in S2 exposing the hydrophobic fusion loop, toexecute fusion of viral and host cell membranes, releasing the viralgenome into the host cell cytoplasm to initiate viral replication.Analysis of large panels of mAbs generated from SARS-CoV-2 infectedindividuals reveals mAbs binding to multiple epitopes across S1 and S2.The majority of mAbs generated against the original strains ofSARS-CoV-2, although able to bind S with high affinity, show little orno neutralizing activity. Genomic surveillance of SARS-CoV-2 hasidentified many thousands of mutations in structural and non-structuralproteins. However, towards the end of 2020, viral variants weredescribed that rapidly became the dominant strains locally and led toglobal spread and their designation of variants of concern (VoC).

Alpha (B.1.1.7) was first identified in the UK, with increasedtransmission. B.1.1.7 harbours 9 amino-acid changes in the spike,including N501Y in the ACE2 interacting surface. Beta (501Y.V2 alsoknown as B.1.351) was first reported in South Africa. Gamma (P.1,501Y.V2) was first reported in Brazil, which have 10 and 12 amino-acidchanges in the spike protein, respectively. Delta was first reportedfrom India and has now spread globally, causing outbreaks in a number ofcountries. Omicron BA.1 was first reported in late November 2021 inSouthern Africa and spread around the world, becoming the dominantvariant in many countries and almost completely displaced Delta.

A succession of sub-lineages of Omicron have emerged, including BA.1.1,BA.2, BA.2.12.1, BA.2.75 and BA.4/5, which have outcompeted precedingstrains to become regionally or globally dominant. Over 30 mutations arefound in the Omicron S protein, including 15 substitutions in the RBD,leading to increased transmissibility (Suzuki et al., 2022 “Attenuatedfusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.” Nature603, 700-705) and widespread large reductions in neutralizing antibodytitres (Dejnirattisai et al., 2022 “SARS-CoV-2 Omicron-B.1.1.529 leadsto widespread escape from neutralizing antibody responses.” Cell 185,467-484 e415).

Omicron BA.2 was reported at nearly the same time as BA.1. Theproportion of Omicron infections caused by BA.2 has been increasing inseveral countries and it became the dominant sub-lineage in Denmark andIndia.

BA.1.1, containing an additional R346K mutation in RBD, at one pointaccounted for about 40% of Omicron sequences globally, and about 35-60%in the UK and the USA (Iketani et al., 2022 “Antibody evasion propertiesof SARS-CoV-2 Omicron sublineages.” Nature 604, 553-556), but was soonoutcompeted by BA.2. BA.2, which contains 8 unique substitutions in S,including 6 within the RBD, and lacks 13 mutations found in BA.1(Nutalai et al., 2022), has become the dominant strain across the worldas of August 2022. Recently, BA.2.12.1 has been identified in multiplecountries, and caused a large regional outbreak in the North America(58% of the sequences as of May 25, 2022) (Del Rio and Malani, 2022,“COVID-19 in 2022—The Beginning of the End or the End of the Beginning?”JAMA 327, 2389-2390).

It is now becoming clear that BA.2 has a small transmission advantageagainst BA.1 although there is no evidence of increased diseaseseverity. In early April 2022, two new Omicron lineages were reportedfrom Gauteng in South Africa and designated BA.4 and BA.5. BA.4 and BA.5(which have identical S sequences) became the dominant Omicron strainsin Gauteng, fueling a new wave of infection in South Africa.

Since June 2022, BA.4/5, which has both higher receptor binding affinityand a markedly enhanced escape from antibody responses (Tuekprakhon etal., 2022 “Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 fromvaccine and BA.1 serum.” Cell 185, 2422-2433 e2413) quickly spread fromSouth Africa across the world and has now become the new globallydominant strain, with BA.5 in the ascendency in many regions. Thesevariants (particularly BA.5) now account for the majority of sequencedcases in many countries.

In early May 2022, a new Omicron sub-lineage designated as BA.2.75emerged in India. This strain has since spread to many countriesincluding the UK, US, Australia, Germany and Canada. However, the trueprevalence of BA.2.75 is difficult to determine as sequencing in manycountries is patchy and has been greatly scaled back.

All of these variants contain multiple mutations in S and includechanges in the RBD, NTD and in some cases the furin cleavage sitebetween S1 and S2. The RBD mutations found in Alpha (N501Y), Beta(K417N, E484K, N501Y), Gamma (K417T, E484K, N501Y) and Delta (L452R,T478K) are located in or closely adjacent to the ACE2 interactingsurface where they have the potential to modulate ACE2 interaction anddisrupt the binding of neutralizing antibodies. Increased affinity ofACE2 interaction has been dominated for Alpha, Beta, Gamma and Delta (7,19, 19, 2-fold, respectively) and may play a role in increasing viraltransmissibility. Omicron contains an unprecedented number of mutationsconcentrated in the Spike (S) gene which carries 30 substitutions plusthe deletion of 6 and insertion of 3 residues. Omicron BA.1 (RBDmutations of G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N,T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H) contains uniquemutations S371L, G446S and G496S and in some isolates R346K (BA.1.1),while BA.2 carries S371F, T376A, D405N and R408S. BA.3 contains nounique mutations relative to BA.1 and BA.2 and appears to be a fusion ofthe two, being BA.1-like at the N terminus and switching to becomeBA.2-like at the C-terminus from the mutation G496S.

BA.2.75 contains multiple mutational changes in the S protein comparedto BA.2, including four substitutions in the NTD (W152R, F157L, I210Vand G257S) and four in the RBD: D339H, G446S, N460K and R493Q.

Three new variants related to BA.2, namely BA.2.11, BA.2.12.1 andBA.2.13, have also been detected in multiple countries. These contain asingle mutation of L452R, L452Q and L452M compared to the BA.2 Spikereceptor-binding domain (RBD) respectively (FIG. 29 ). Among them,BA.2.12.1, first identified in New York, became dominant in the US,accounting for about 58% of SARS-CoV-2 isolates as of May 25, 2022.While L452R is found in Delta and Kappa variants, and L452Q in Lambda,L452M is novel.

Considering the physico-chemical properties of the side chain of residue452, BA.2.13 would be expected to be a relatively modest change; L to Mwill increase the size of the side chain but it remains hydrophobic. Lto Q in BA.2.12.1 introduces some polar character, whilst BA.2.11 is themost radical with L to R introducing a large basic amino acid.

Further variants, BA.4 and BA.5, which have identical S sequences,appear to have evolved from BA.2. The sequences of BA.4 and BA.5 arehighly related to the sequence of BA.2, but contain additionalmutations. In particular, residues 69 and 70 of the NTD have beendeleted (also found in Alpha, BA.1 and BA.3) and they contain twoadditional substitutions in the RBD: L452R (also found in Delta) andF486V. Finally BA.4 and BA.5 lack the Q493R change seen in BA.1 andBA.2, reverting to Q493 as in the Victoria/Wuhan strain. When looking atthe RBD, BA.4 and BA.5 have assembled mutations at all of the previouslydescribed positions in the VoC Alpha (N501Y), Beta (K417N, E484K,N501Y), Gamma (K417T, E484K, N501Y), Delta (L452, T478K), the onlydifference is E484A in BA.4 and BA.5 rather than E484K Beta and Gamma.

As of September 2022, a new variant related to BA.4/5, designatedBA.4.6, has emerged and expanded in the United States where BA.5dominates (87.5% prevalence as of 10 Sep. 2022, tripling from less than2% of sequences in early July 2022 to over 6% in mid-August 2022).Compared to BA.4/5, BA.4.6 contains two extra mutations in the Spikeprotein (S), R346T in the RBD and N658S in the C-terminal domain. TheR346T mutation has raised concern for enhanced antibody evasion overBA.4/5, as the R346K mutation in BA.1.1 reduced serum neutralisationcompared to BA.1 and impaired the activity of a number of monoclonalantibodies (mAbs) (Nutalai, et al., 2022). SARS-CoV-2 detection kitsusing monoclonal antibodies have also been developed. Examples includelateral flow tests by, e.g. Innova (SARS-CoV-2 Antigen Rapid QualitativeTest) and Quidel (Sofia 2 SARS Antigen FIA). However, these tests arereported to be highly inaccurate.

As of January 2023, further variants have emerged such as BQ.1 and XBB,which carry up to 8 additional RBD amino-acid substitutions compared toBA.2.

Structure function mapping of panels of monoclonal antibodies (mAbs)isolated from infected cases has led to considerable understanding ofthe antigenicity of S and mechanisms of neutralization. The majority ofpotent neutralizing antibodies bind at or in close proximity to thefootprint of ACE2 and function by blocking ACE2 interaction, therebypreventing cellular attachment and infection. A second site ofinteraction of potent mAbs is in proximity to N-linked glycan atposition N343, exemplified by S309, these antibodies do not block ACE2interaction but may function to destabilize the S trimer. The thirdgroup of potent mAbs bind to the N-terminal domain in 51 and their modeof action is at present unclear. Another RBD epitope of potentialinterest lies outside of the ACE2 footprint and whilst mAbs binding hereare not potent neutralizers they can nevertheless effectively protect invivo (Huo et al., 2020; Sun et al., 2021; Yuan et al., 2020; Zhou etal., 2020).

Following BA.5 several new trends were observed in the evolution ofOmicron: i) the emergence of ‘second generation’ BA.2 variants(including derivatives of BA.5)—variants with long phylogenetic branchlengths, multiple antigenic mutations and a lack of geneticintermediates, for example BA.2.75, BJ.1, BS.1, BA.2.10.4 and BA.2.3.20(van der Straten et al. 2022. Immunity 55, 1725-1731) and ii)accelerated antigenic drift, seen both in BA.5 (Tuekprakhon et al.,2022) and within these second generation BA.2 lineages, notably BQ.1 andBA.2.75 (https://nextstrain.org/nextclade/sars-cov-2/21L). Finally,recombination between two of these second-generation variants (BJ.1 andBM.1.1.1) has produced XBB. Many of these variants show a large degreeof convergent evolution in known antigenic RBD residues, and mutationslie in areas that may threaten the binding of neutralizing antibodies,leading to further escape from protection from infection afforded byvaccine or previous SARS-CoV-2 infection, including prior Omicroninfection.

At present a number of lineages are growing rapidly from within both theBA.2 and BA.5 branches. Most striking is the large degree of convergentevolution, particularly at antigenic RBD positions such as 346, 444,446, 452, 460, 486, 490, and 494. These lineages include examples fromthe BA.4/5 branch (which naturally contains L452R, F486V and thereversion R493Q), such as BA.4.6 and BF.7 (R346T), BA.4.7 (R346S), BQ.1(K444T, N460K) and BQ.1.1 (R346T, K444T, N460K); from the BA.2.75 branch(which naturally contains G446S, N460K and the reversion R493Q),BA.2.75.2 (R346T and F486V), BN.1 (R346T, K356T, F490S). There are alsoexamples of several other second generation BA.2 variant lines such asBJ.1 (aka BA.2.10.1.1; R346T, L368I, V445P, G446S, V483A and F490V),BA.2.10.4 (G446S, F486P, S494P and the R493Q reversion), BS.1(BA.2.3.2.1; R346T, L452R, N460K, G476S), BA.2.3.20 (K444R, N450D,L452M, N460K, E484R and the Q493R reversion), and finally a BA.2.75×BJ.1recombinant, XBB (which relative to BA.2 contains R346T, L368I, V445P,G446S, N460K, F486S, F490S).

These second-generation BA.2 variants have become dominant globally,with BQ.1 alone accounting for 50% of infections as of 27 Dec. 2022(https://cov-spectrum.org/explore/World/AllSamples/Past6M) and XBB.1.5(XBB.1+F486P) expanding rapidly in North America).

Outside the RBD the degree of convergent evolution is lesser but stillpresent. Many of the second-generation BA.2 variant lineages containdeletions or mutations in the NTD, often similar to that seen in theVoCs, for example A-144 in BJ.1 and BA.2.10.4 (previously seen in Alphaand BA.1) and NSP12 G671S in BJ.1, BA.2.75 and BA.2.10.4 (previouslyseen in Delta).

All currently approved SARS-CoV-2 vaccines are designed to induceantibody (and T-cell) responses to S and contain the S sequence found inthe original Wuhan strain.

There is therefore particular concern as to whether the S mutations inthe VoCs could cause immune escape, leading to vaccine failure orsusceptibility to repeat infections in previously infected individuals.

The extensive mutational burden in Omicron S disrupts the activity ofthe majority of mAb binding to the three sites of binding of potentantibodies described above, the ACE-2 footprint, around the N343 glycanand the NTD. This leads to severe knock down or complete loss of theneutralizing capacity of serum from natural infection or vaccination,which has contributed to the increased transmissibility and explosivespread of Omicron.

It is an object of the invention to identify further and improvedantibodies useful for preventing, treating and/or diagnosing coronavirusinfections, and diseases and/or complications associated withcoronavirus infections, including COVID-19, especially the Omicronvariants of concern (VoCs) and as-yet-unidentified variants havingfurther mutations in the ACE-2 footprint, RBD and/or NTD in the spikeprotein of SARS-CoV-2.

SUMMARY OF THE INVENTION

The inventors identified 28 human monoclonal antibodies (mAbs)recognizing the spike protein of SARS-CoV-2 (see Table 3). Theseantibodies showed potent neutralisation activity against SARS-CoV-2.Some of the Table 3 antibodies demonstrated potent neutralizationeffects that were broadly effective against the hCoV-19/Wuhan/WIV04/2019strain, as well as SARS-CoV-2 strains from various lineages, such asVictoria (Wuhan+S247R), Alpha, Beta, Gamma, Delta, Omicron, includingOmicron BA.2.11, Omicron BA.2.12.1, Omicron BA.2.13, Omicron OmicronBA.2.3.20, Omicron BA.2.10.4, Omicron BA.1, Omicron BA.1.1, OmicronBA.2, Omicron BA.2.75, BA.2.75.2, Omicron BA.3, Omicron BA.4.6, OmicronBA.4/5, Omicron BJ.1, Omicron BS.1, Omicron BN.1, Omicron XBB, and/orOmicron XBB.1 strains.

Many of the Table 3 mAbs used public V-genes (V-genes shared by themajority of the population). The inventors have previously shown that itis possible to generate further antibodies by swapping the light andheavy chains of the antibodies in Tables 1, 2 and 3 which are derivedfrom the same public V-genes. Antibodies derived from the same publicV-genes provided particularly useful mixed-chain antibodies.

In particular, the inventors found that antibodies Omi02, Omi03, Omi12,Omi18, Omi28, Omi39 and Omi42 were particularly effective atcross-neutralising SARS-CoV-2 strains Victoria, Alpha, Beta, Gamma,Delta and Omicron.

Accordingly, the invention provides an antibody capable of binding tothe spike protein of coronavirus SARS-CoV-2, wherein the antibodycomprises at least three CDRs of any one of the 28 antibodies in Table3.

The invention provides an antibody capable of binding to the spikeprotein of coronavirus SARS-CoV-2, wherein the antibody comprises atleast three CDRs of antibody Omi12, or of any one of the 27 antibodiesin Table 3.

The invention also provides a combination of antibodies comprising twoor more antibodies according to the invention.

The invention also provides a combination of antibodies comprising (a)an antibody of the invention; and (b) an antibody comprising at leastthree CDRs of an antibody in Table 1 or Table 2. For example, theantibody may comprise (i) at least four, five, or all six CDRs of anantibody in Table 1 or Table 2; (ii) a heavy chain variable domaincomprising or consist of an amino acid sequence having at least 80%sequence identity to the heavy chain variable domain of an antibody inTable 1 or Table 2; (iii) a light chain variable domain comprising orconsisting of an amino acid sequence having at least 80% sequenceidentity to the light chain variable domain of an antibody in Table 1 orTable 2; and/or (iv) a heavy chain variable domain and a light chainvariable domain comprising or consisting of an amino acid sequencehaving at least 80% identity to the heavy chain variable domain andlight chain domain, respectively, of an antibody in Table 1 or Table 2.

The invention also provides one or more polynucleotides encoding anantibody of the invention, one or more vectors comprising saidpolynucleotides, or a host cell comprising said vectors.

The invention also provides a method for producing an antibody that iscapable of binding to the spike protein of coronavirus SARS-CoV-2,comprising culturing the host cell of the invention and isolating theantibody from said culture.

The invention also provides a pharmaceutical composition comprising: (a)an antibody or a combination of antibodies of the invention, and (b) atleast one pharmaceutically acceptable diluent or carrier.

The invention also provides an antibody, a combination of antibodies ora pharmaceutical composition of the invention, for use in a method fortreatment of the human or animal body by therapy.

The invention also provides an antibody, a combination of antibodies ora pharmaceutical composition of the invention, for use in a method oftreating or preventing coronavirus infection, or a disease orcomplication associated with coronavirus infection.

The invention also provides a method of treating or preventingcoronavirus infection, or a disease or complication associated withcoronavirus infection in a subject, comprising administering atherapeutically effective amount of an antibody, a combination ofantibodies or the pharmaceutical composition of the invention, to saidsubject.

The invention also provides a method of identifying the presence ofcoronavirus, or a protein fragment thereof, in a sample, comprising (i)contacting the sample with an antibody or combination of antibodies ofthe invention, and (ii) detecting the presence or absence of anantibody-antigen complex, wherein the presence of the antibody-antigencomplex indicates the presence of coronavirus, or a fragment thereof, inthe sample.

The invention also provides a method of treating or preventingcoronavirus infection, or a disease or complication associatedtherewith, in a subject, comprising identifying the presence ofcoronavirus according to the method of the invention, and treating thesubject with the antibody or combination according to the invention, ananti-viral or an anti-inflammatory agent.

The invention also provides the use of an antibody, a combination ofantibodies or a pharmaceutical composition of the invention, forpreventing, treating and/or diagnosing coronavirus infection, or adisease or complication associated therewith.

The invention also provides the use of an antibody, a combination ofantibodies or a pharmaceutical composition of the invention, for themanufacture of a medicament for treating or preventing coronavirusinfection, or a disease or complication associated therewith.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 . The BA.2 sub-lineage of Omicron and generation of a panel ofOmicron mAb.

FIG. 1 relates only to the first 22 Omicron antibodies disclosed inTables 13 and 14 (i.e. Omi02 to Omi35). (A) FRNT50 titres againstVictoria and Omicron BA.1 from the donors for the production of OmicronmAb are shown. (B) FACS plots showing the sorting of B cells using fulllength Omicron S. (C) Proportion of RBD and NTD binding antibodies foundin the Omicron mAb compared to early pandemic mAb. (D) Heavy and Lightchain variable gene usage. (E) Somatic mutations found in the potentOmicron mAb (FRNT50<100 ng/ml) compared to the early pandemic set.

FIGS. 2A-2C. Neutralization curves using Omicron mAb. (2A) Victoria,Alpha, Beta, Gamma, Delta and Omicron BA.1 viruses. (2B) neutralizationof Victoria, BA.1, BA.1.1, BA.2 and BA.3 pseudoviruses by Omicron mAb.(2C) neutralization of Victoria, BA.1, BA.1.1, BA.2 and BA.3pseudoviruses by antibodies being developed for commercial use.

FIG. 3 . Neutralization of Victoria, BA.1, BA.1.1, BA.2 and BA.3pseudoviruses. Neutralization of Victoria, BA.1, BA.1.1, BA.2 and BA.3pseudoviruses 28 days following the second and third doses of (A)AZD1222 (n=41), (B) BNT162b2 (n=20). (C) Live virus neutralizationassays with Victoria, Alpha, Beta, Gamma, Delta and Omicron virusesusing sera obtained <14 days and >21 days following symptom onset (D)Neutralization of Victoria, BA.1, BA.1.1, BA.2 and BA.3 pseudoviruses byearly and late sera. Geometric mean titres are shown above each column.The Wilcoxon matched-pairs signed rank test (A and B) and Mann-Whitneytest (C and D) were used for the analysis and two-tailed P values werecalculated.

FIGS. 4A-4B. Pseudoviral neutralization curves. Pseudoviralneutralization curves for BA.1, BA.1.1, BA.2 and BA.3 on Early pandemicmAb (4B) Beta mAb.

FIG. 5 . Neutralization titres on the indicated viruses related to FIG.3 (A) live viruses (B) pseudoviruses. Geometric mean titres are shownabove each column. The Wilcoxon matched-pairs signed rank test was usedfor the analysis and two-tailed P values were calculated. (C)pseudovirus neutralization curves for selected VH1-58 mAb and controlVH3-53 mAb 222 against Victoria and Iota (S477N).

FIG. 6 . Structure of BA.1 RBD with Omi-12 Fab. (A) Two ternarycomplexes of Omi-12 and Beta-54 Fabs with BA.1 (produced by fitting thehigh-resolution structures of BA.1 RBD, Omi-12 and Beta-54 to thelower-resolution ternary complex density) in the crystal asymmetric unitare compared by overlapping the RBD. Fabs in one complex are in brightcolours (cartoon depiction HC red, LC blue) and the other in palecolours. (B) The binding mode of Omi-12. (C) Close-up of the bindingdifferences of Omi-12 with Fab 253 complexed with early pandemic RBD(pale blue) and Beta-47 with Beta RBD (pale cyan). (D) The somaticmutation V53P contributes to re-folding of the H3 loop so that Q493R canbe accommodated in Omi-12.

FIG. 7 . Pseudoviral neutralization assays of BA.4/5 by vaccine and BA.1immune serum. IC50 values for the indicated viruses using serum obtainedfrom vaccinees 28 days following their third dose of vaccine (A)AstraZeneca AZD AZD 1222 (n=41), (B) 4 weeks after the third dose ofPfizer BNT162b2 (n=20). Serum from volunteers suffering breakthroughBA.1 infection volunteer taken (C) early≤1 14 (n=12) days from symptomonset (median 13 days) (D) late ≥21 days from symptom onset (median 38days) n=16. Comparison is made with neutralization titres to Victoria(an early pandemic strain), BA.1, BA.1.1, BA.2 and BA.3. Geometric meantitres are shown above each column. The Wilcoxon matched-pairs signedrank test was used for the analysis and two-tailed P values werecalculated.

FIG. 8 . Pseudoviral neutralization assays against Omicron andcommercial monoclonal antibodies. Neutralization curve for a panel of 28monoclonal antibodies made from samples taken from vaccinees infectedwith BA.1. Titration curves for BA.1 are compared with BA.1, BA.1.1,BA.2 and BA.3. mAb proposed to be affected by the L452R and F486L areindicated.

FIG. 9 . The Omicron sub-lineage compared to BA.4/5. (A) Comparison of Sprotein mutations of Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4/5 withNTD and RBD boundaries indicated. (B) Position of RBD mutations (greysurface with the ACE2 footprint in dark green). Mutations common to allOmicron lineages are shown in white (Q493R which is reverted in BA.4/5is shown with a cross), those common to BA.1 and BA.1.1 in cyan, thoseunique to BA.1.1 in blue and those unique to BA.2 in magenta. Residue371 (yellow) is mutated in all Omicron viruses but differs between BA.1and BA.2. The N343 glycan is shown as sticks with a transparent surface

FIG. 10 . Surface plasmon resonance (SPR) analysis of interactionbetween BA.2 or BA.4/5 RBD and selected mAbs. (A) Binding of BA.4/5 RBDis severely reduced compared to that of BA.2, so that the binding couldnot be accurately determined, as shown by a single-injection of 200 nMRBD over sample flow cells containing IgG Omi-31. (B-C; E-I) Sensorgrams(Red: original binding curve; black: fitted curve) showing theinteractions between BA.2 or BA.4/5 RBD and selected mAbs, with kineticsdata shown. (D) Determination of the affinity of BA.4/5 RBD to Omi-12using a 1:1 binding equilibrium analysis.

FIG. 11 . Interactions between mAb and BA.4/5 mutation sites. Overallstructure (left panel) and interactions (≤4 Å) with BA.4/5 mutationsites (right panel) for (A) BA.1-RBD/Omi-31 (PDB 7ZFB), (B)BA.1-RBD/Omi-32 (PDB 7ZFE), (C) BA.1-RBD/Omi-25 (PDB 7ZFD), (D)BA.1-RBD/Omi-42 (PDB7ZR7), (E) Wuhan-RBD/AZD8895 (PDB 7L7D) and (F)BA.1-RBD/Omi-3 (PDB 7ZF3) complexes. In the left panels RBD is shown assurface representation, with BA.4/5 mutation sites highlighted inmagenta and the additional two mutation sites of BA.4/5 at 452 and 486in cyan, and Fab LC as blue and HC as red ribbons. In the right panel,side chains of RBD, Fab HC and LC are drawn as grey, red and bluesticks, respectively. In (B) L452R (green sticks) are modelled to show asalt bridge to D99 of CDR-H3 may be formed (yellow broken sticks). (D)Beta-RBD/Omi-42 complex showing the Fab does not contact any of the twoBA.4/5 mutation sites.

FIG. 12 . ACE2 RBD affinity. (A)-(D) SPR sensorgrams showing ACE2binding of BA.4/5 RBD (A) in comparison to binding to ancestral (Wuhan)(B), BA.1 (C) and BA.2 RBD (D). The data for Wuhan, BA.1 and BA.2 havebeen reported previously in (Nutalai et al., 2022). (E)-(G)Electrostatic surfaces, (E) from left to right, early pandemic, Deltaand BA.1 RBD respectively, (F) open book view of BA.2 RBD and ACE2 ofthe BA.2 RBD/ACE2 complex (PDB 7ZF7), and (G) BA.4/5 RBD (modelled basedon the structure of BA.2 RBD). The lozenges on ACE2 and RBD show theinteraction areas.

FIG. 13 . Antigenic mapping. (A) Neutralization data and model (logtitre values) used to calculate antigenic maps in (B). Columns representsera collected from inoculated volunteers or infected patients. Rows arechallenge strains: Victoria, Alpha, Delta, Beta, Gamma, BA.1, BA1.1,BA.2, BA.3 and BA.4/5 in order. Values are colored according to theirdeviation from the reference value; the reference value is calculated ona serum-type basis as the average of neutralization titres from the rowwhich gives this the highest value. (B) Orthogonal views of theantigenic map showing BA.4/5 in the context of the positions of previousVoC and BA.1, BA.1.1, BA.1 and BA.2, calculated from pseudovirusneutralisation data. Distance between two positions is proportional tothe reduction in neutralisation titre when one of the correspondingstrains is challenged with serum derived by infection by the other. FIG.6 . ACE2/RBD affinity and antigenic mapping

FIG. 14 . Neutralization curves for VH1-58 mAb. Pseudoviralneutralization curves for early pandemic mAb 253 (Dejnirattisai et al.,2021a) and Beta-47 (Liu et al., 2021b) against Victoria and the panel ofOmicron lineage constructs.

FIG. 15 . Surface plasmon resonance (SPR) analysis of interactionbetween BA.2 or BA.4/5 RBD and selected mAbs. (A-F) Sensorgrams (Red:original binding curve; black: fitted curve) showing the interactionsbetween BA.2 or BA.4/5 RBD and selected mAbs, with kinetics data shown.(G-K) Binding of BA.4/5 RBD is severely reduced compared to that ofBA.2, so that the binding could not be accurately determined, as shownby a single-injection of 200 nM RBD over sample flow cells containingthe mAb indicated.

FIG. 16 . Sequence changes in BA.2.75 compared to other Omicronsub-lineages. (A) Sequence alignments of BA.2.75 together with Omicronsublineages Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4/5. Boundaries ofthe NTD and RBD are marked. (B) Surface representation of mutatedresidues in BA.2.75 RBD in comparison to BA.2 RBD. Position of BA.2 RBDmutations (grey surface with the ACE2 footprint in dark green) are shownand residues mutated in BA.2.75 are shown in orange and labelled.

FIG. 17 . Pseudoviral neutralization assays of BA.2.75 by vaccine andBA.1 and BA.2 immune serum. IC50 values for the indicated viruses usingserum obtained from vaccinees 28 days following their third dose ofvaccine (A) Pfizer BNT162b2 (n=22). (B) AstraZeneca AZD AZD1222 (n=41).(C, D) Serum from volunteers suffering vaccine breakthrough BA.1 (n=16)or BA.2 (n=23) infections. (EC) IC50 values for single RBD pointmutations inserted into the BA.2 pseudovirus using Pfizer BNT162b2 serum(n=22) Geometric mean titres are shown above each column. The Wilcoxonmatched-pairs signed rank test was used for the analysis and two-tailedP values were calculated.

FIG. 18 . ACE2/RBD affinity. SPR sensorgrams showing ACE2 binding ofBA.2.75 RBD using ACE2-Fc (A) or biotinylated ACE2 as ligand (B) incomparison to binding to the RBD of BA.2 (C), BA.4/5 (D), Alpha (E) andBA.2+R493Q (F). The data for BA.2, BA.4/5 and Alpha have been reportedpreviously in Nutalai et al., 2022, Tuekprakhon et al., 2022 andDejnirattisai et al., 2022, respectively.

FIG. 19 . Pseudoviral neutralization assays against monoclonalantibodies. (A) Neutralization curves for a panel of 28 mAb made fromsamples taken from vaccinees infected with BA.1. Titration curves forBA.2.75 are compared with Victoria, BA.1, BA.1.1, BA.2 and BA.4/5. IC50titres are shown in Table 22. (B) Pseudoviral neutralization assays withmAbs developed for human use. IC50 titres are shown in Table 23. Datafor Victoria, BA.1, BA.1.1 and BA.2 and BA.4/5 are used for comparisonand taken from Tuekprakhon et al., 2022

FIG. 20 . The Structure of BA.2.75 RBD/ACE2 complex. (A) The overallstructure of the BA.2.75 RBD/ACE2 complex. ACE2 is shown as greenribbons and the RBD as surface with mutations common to BA.2 highlightedin magenta and different in orange. (B) BA.2.75 RBD (grey) and ACE2(green) interface compared with that of BA.2 and ACE2 (both in salmon).Closeups show interactions of Q496R and Q493 (R493 in BA.2) with ACE2.

FIG. 21 Interactions between mAb and BA.75 mutation sites. (A) Front andback views of the binding modes of Omi-3 (PDB, 7ZF3) and Omi-18 (PDB,7ZFC) complexed with omicron BA.1 RBD by overlapping the RBD. The RBD isshown as grey surface representation with mutations common to both BA.2and BA.2.75 coloured in magenta, and the four mutations differentbetween the two in cyan. VHs and VLs are shown as ribbons and colouredin red and blue for Omi-3, and light blue and salmon for Omi-18,respectively. (B) Interactions between N460 of the RBD and CDR-H2 of theFabs. (C) Contacts between R493 of the RBD and CDR-H3 of the Fabs. In(B) and (C) The RBD associated with Omi-3 is in grey and Omi-18 in cyan,and the colours of the Fabs are as in (A). (D) AZD 1061 bound with theancestral SARS-CoV-2 RBD (PDB, 7L7E) and (E) contacts between G446 ofthe RBD and CDR-L2 of the Fab. (E) AZD8895 bound with the ancestralSARS-CoV-2 spike RBD (PDB, 7L7E) and (F) contacts between Q493 of theRBD and CDR-H2 of the Fab. In (D)-(F), RBD is drawn and coloured as in(A), HC is in red and LC in blue.

FIG. 22 . Antigenic mapping. (A) Orthogonal views of the antigenic mapshowing BA.2.75 in the context of the positions of previous VoC andBA.1, BA.1.1, BA.1 and BA.2, calculated from pseudovirus neutralisationdata. Distance between two positions is proportional to the reduction inneutralisation titre when one of the corresponding strains is challengedwith serum derived by infection by the other. No scale is provided sincethe figures are projections of a three-dimensional distribution, howeverthe variation can be calibrated by comparison with (i) BA.1 to BA.2which is 2.93×reduced and (ii) BA.2 to BA.4/5 which is 3.03×reduced. (B)As (A) but including only Omicron sublineages and early pandemic virusesto allow more accurate projection of this subset into three-dimensions.Note that responses of these viruses against all sera were included inthe calculations.

FIG. 23 . Pseudoviral neutralization assays against monoclonalantibodies. (A) Neutralization curves for a panel of 28 monoclonalantibodies made from samples taken from vaccinees infected with BA.1.Titration curves for single mutations of BA.2.75 in the BA.2 backboneare compared with BA.2 and BA.2.75. IC50 titres are shown in Table 24.

FIG. 24 . Surface plasmon resonance (SPR) analysis of interactionbetween BA.2 or BA.2.75 RBD and selected mAbs. (A) Binding of Omi-29(IGHV3-53) to BA.2.75 RBD is severely reduced compared to that of BA.2,as shown by a single-injection of 1 μM Omi-29 Fab over sample flow cellscontaining biotinylated BA.2 or BA.2.75 RBD. (B) Binding of Omi-36(IGHV3-66) to BA.2.75 RBD is severely reduced compared to that of BA.2,as shown by a single-injection of 0.2 μM BA.2 or BA.2.75 RBD over sampleflow cells containing Omi-36 in the IgG form. (C-H) Sensorgrams(Red/Coloured: original binding curve; black: fitted curve) showing theinteractions between BA.2 or BA.4/5 RBD and selected mAbs, with kineticsdata shown.

FIG. 25 . Neutralization of BA.2.75 by panels of convalescent serumcollected from infection with historic variants. Neutralization titresof the indicated sera against BA.2.75 and the indicated pseudoviruses.Data apart from BA.2.75 has been taken from Tuekprakhon et al., 2022.

FIG. 26 . Primers for site-directed PCR mutagenesis of the BA.2.75 RBDSite-directed PCR mutagenesis was performed using the BA.2 Spikeconstruct as the template. D339H, G446S, N460K and R493Q mutations wereintroduced using the primers shown.

FIG. 27 . Characterisation of BA.2.11, BA.2.12.1 and BA.2.13 bypseudoviral neutralization assays, surface plasm on resonance andstructural analysis. (a), (b) IC50 values for the indicated virusesusing serum obtained 4 weeks after a third dose of vaccine (a)AstraZeneca AZD1222 (n=41), (b) Pfizer BNT162b2 (n=18). (c)Neutralization titres of serum from vaccinated volunteers sufferingbreakthrough BA.1 infection were taken. Comparison is made withneutralization titers to Victoria, BA.1, BA.1.1, BA.2 and BA.4/5previously reported in Tuekprakhon et al. (2022). Geometric mean titersare shown above each column. The Wilcoxon matched-pairs signed-rank testwas used for the analysis, and two-tailed p values were calculated.(d-g) SPR sensorgrams (red: experimental binding curve; black: fittedcurve) showing ACE2 binding of the RBD of BA.2.11 (e), BA.2.12.1 (f),BA.2.13 (g) in comparison with binding to BA.2 RBD (h), with kineticsdata shown. The data for BA.2 RBD were reported in Nutalai et al.(2022). (h-m) Crystal structure of BA.2.12.1 RBD/Beta-27/NbCl complex.(h) Overall structure shown as Ca traces with RBD (grey), Beta-27 HC(red) and LC (blue), and NbCl (yellow). Cαs of residues L452Q, F486 andQ493R (L, F and R in BA.2, R, V and Q in BA.4/5) are shown as spheres.(i) Comparison of Beta-27 binding modes in the BA.2.12.1RBD/Beta-27/NbCl (RBD as surface representation, HC in red and LC inblue), BA.4/5 RBD/Beta-27/NbCl (cyan, PDB 7ZXU) and Beta RBD/Beta-27(green, PDB 7PS 1) complexes by overlapping the RBDs. Apart from theflexible N- and C-terminal regions of RBD, significant differences occurat N-terminus and CDR-H1 of the Fab HC, α2 helix, 371-375 loop and G446loop of the RBD. CDR-L3 has double conformations in the BA.4/5 RBDcomplex, and a single conformation in other two complexes (i). The HCN-terminus and CDR-H1 which contacts residue 486 of the RBD differs tothose in both Beta and BA.4/5 RBD complexes, the latter contains F486Vmutation. The differences are likely caused by contacts from a symmetryrelated C1 nanobody shown as grey bonds in (j). (k) The structuraldifference at G446 loop in the BA.4/5 RBD is also induced by crystalcontact. (1) 371-375 loop that carries S371F, S373P and S375F mutationsin BA.2.12.1 and BA.4/5 RBDs is stabilized by interactions with CDR-H3of NbCl. (m) Superimposition of BA.2.12.1 (grey), BA.2 (green, PDB 7ZF9)and BA.4/5 (cyan) RBDs. (n) Mutations at 452 do not introducesignificant local structural changes. R452 in BA.4/5 has a doubleconformation.

FIG. 28 . Pseudoviral neutralization assays of BA.4.6 by vaccine. BA.1,BA.2, BA.4.5 immune serum (a-d) and monoclonal antibodies (e-f). IC50values for the indicated viruses using serum obtained from vaccinees 28days following their third dose of Pfizer BNT162b2 vaccine (n=22, a).1050 values for the indicated viruses against serum from volunteerssuffering vaccine breakthrough BA.1 (n=14, b), BA.2 (n=23, c) and BA.4/5(n=11, d) infections. Geometric mean titres are shown above each column.The Wilcoxon matched-pairs signed rank test was used for the analysisand two-tailed P values were calculated. Neutralization curves for apanel of 28 monoclonal antibodies made from samples taken from vaccineesinfected with BA.1 (e) against BA.4.6 were compared with Victoria, BA.1,BA.1.1, BA.2, BA.4/5 and BA.2.75 variants. Neutralization curves for apanel of 14 commercial monoclonal antibodies against same variants (e).IC50 values are shown in Table 29A and 29B.

FIG. 29 . Pseudoviral neutralization assays. Pseudoviral neutralizationassays against Omicron monoclonal antibodies, related to Table 26 where1050 titers are shown. Neutralization curves for a panel of 27monoclonal antibodies made from samples taken from vaccinees infectedwith BA.1. Titration curves for BA.2.11, BA.2.12.1 and BA.2.13 arecompared with BA.2.

FIG. 30 . Surface plasmon resonance (SPR) analysis of the interactionbetween BA.2.12.1 or BA.2 RBD and selected mAbs (Omi-6 and Omi-31). (a)Determination of the affinity of BA.2.12.1 RBD to Omi-6 using a 1:1binding equilibrium analysis. (b), (c), (d) Sensorgrams (red: originalbinding curve; black: fitted curve) showing the interactions betweenBA.2.12.1 or BA.2 RBD and selected mAbs, with kinetics data shown.

FIG. 31 . Neutralization assays. Neutralization curves using lentiviruspseudotyped with the S gene of indicated BA.2 sub-lineages (A) Omi-mAb,(B) Commercial mAb. See also Table 32. The “BA.4+all” variant is asynthetic variant, designed following the assessment of differentmutations that occur in the SARS-CoV-2 Omicron S gene. These mutationswere combined and incorporated into an Omicron BA.4 S gene to producethe artificial S gene called “BA.4+all”. This variant was created solelyas an experimental tool and does not exist in nature, nor corresponds tothe S gene of any circulating SARs-Cov-2 variant.

FIG. 32 . Serum neutralization IC50 titres (fold dilution) of lentiviruspseudotyped with the S gene of the indicated BA.2 sub-lineages. (A)Serum obtained 28 days following the third dose of BNT162b2 vaccine orfollowing infection with (B) BA.1 (C) BA.2 or (D) BA.4/5. Geometric meantitres are shown above each column. The Wilcoxon matched-pairs signedrank test (C and D) and Mann-Whitney test (E) were used and two-tailed Pvalues calculated.

FIG. 33 . Heatmaps of antibody binding. Heatmap showing the IC50 (μg/ml)of various antibodies against the Victoria and Beta strains in bothvaccinated and unvaccinated samples.

FIG. 34 . Neutralization assays. Neutralization curves using lentiviruspseudotyped with the S gene of the indicated BA.2 sub-lineages.

FIG. 35 . Heat map of IC50 neutralization titres for the panel of BA.1(Omi) mAb. Pseudoviral neutralization IC50 titres for indicated mAbagainst a panel of pseudoviruses expressing variant S sequences. Livevirus IC50 values against variants found earlier in the pandemic areincluded for comparison. Data for live virus assays and pseudoviral datafor Victoria, BA.2 and BA.4/5 were previously reported in Tuekprakon etal. (2022).

DETAILED DESCRIPTION OF THE INVENTION Antibodies of the Invention

An antibody of the invention specifically binds to the spike protein ofSAR-CoV-2.

In particular, it specifically binds to the S1 subunit of the spikeprotein, such as the receptor binding domain (RBD) or N-terminal domain(NTD).

An antibody of the invention may comprise at least three CDRs of anantibody in Table 3. The antibody may comprise at least four, five, orall six CDRs of an antibody in Table 3. The antibody may comprise aheavy chain variable domain comprising or consisting of an amino acidsequence having at least 80% sequence identity to the heavy chainvariable domain of an antibody in Table 3. The antibody may comprise alight chain variable domain comprising or consisting of an amino acidsequence having at least 80% sequence identity to the light chainvariable domain of an antibody in Table 3. The antibody may comprise aheavy chain variable domain and a light chain variable domain comprisingor consisting of an amino acid sequence having at least 80% identity tothe heavy chain variable domain and light chain domain, respectively, ofan antibody in Table 3. The antibody may be any one of the antibodies inTable 3.

Table 3 lists 28 individual antibodies that were identified fromrecovered breakthrough Omicron SARS-CoV-2-infected patients, whom hadalready been received two doses of the Pfizer vaccine. Table 1 lists 42individual antibodies that were previously identified from recoveredCOVID-19 patients [Dejnirattisai, Wanwisa, et al. “The antigenic anatomyof SARS-CoV-2 receptor binding domain.” Cell 184(8) (2021): 2183-2200;Supasa, Piyada, et al. “Reduced neutralization of SARS-CoV-2 B. 1.1.7variant by convalescent and vaccine sera.” Cell 184(8) (2021):2201-2211; Zhou, Daming, et al. “Evidence of escape of SARS-CoV-2variant B.1.351 from natural and vaccine-induced sera.” Cell 184(9)(2021): 2348-2361; Dejnirattisai, Wanwisa, et al. “Antibody evasion bythe P.1 strain of SARS-CoV-2.” Cell 184(11) (2021): 2939-2954; Liu,Chang, et al. “Reduced neutralization of SARS-CoV-2 B. 1.617 by vaccineand convalescent serum.” Cell 184(16) (2021): 4220-4236.]. Table 2 lists28 individual antibodies that were previously identified from recoveredBeta SARS-CoV-2 infected patients [Liu, C et al. “The antibody responseto SARS-CoV-2 Beta underscores the antigenic distance to othervariants”. Cell host & microbe 30(1)(2021): 53-68]. The antibodies inTable 1 are also referred to herein with a pre-fix “COVOX”, e.g.COVOX-222. The antibodies in Table 2 are also referred to with a pre-fix“β”, e.g. “β50”. The antibodies in Table 3 are also referred to with apre-fix “O”, e.g. “O02”. Tables 1 to 3 list the SEQ ID NOs for the heavychain variable region and light chain variable region nucleotide andamino acid sequences, and the complementarity determining regions (CDRs)of the variable chains, of each of the antibodies.

The antibody in Table 3 may be selected from the group consisting of:Omi03, Omi12, Omi02, Omi39, Omi42, Omi16, Omi18, Omi20, Omi 23, Omi28,Omi08, Omi17, Omi29, Omi36 and Omi38. These antibodies were surprisinglyfound to retain strong neutralisation of the live SARS-CoV-2 variantstrains Victoria, Alpha, Beta, Gamma, Delta and Omicron (e.g. an IC50 of≤0.1 μg/ml against all live strains tested).

The antibody in Table 3 may be selected from the group consisting of:Omi03, Omi12, Omi02, Omi39, Omi42, Omi16, Omi18, Omi20, Omi 23, Omi28and Omi 08. These antibodies were surprisingly found to retain strongneutralisation of the live SARS-CoV-2 variant strains Victoria, Alpha,Beta, Gamma, Delta and Omicron (e.g. an IC50 of ≤0.05 μg/ml against alllive strains tested).

The antibody in Table 3 may be selected from the group consisting of:Omi03, Omi12, Omi02, Omi39 and Omi42. These antibodies were surprisinglyfound to retain strong neutralisation of the live SARS-CoV-2 variantstrains Victoria, Alpha, Beta, Gamma, Delta and Omicron (e.g. an IC50 of≤0.02 μg/ml against all live strains tested).

The antibody in Table 3 may be selected from the group consisting of:Omi03 and Omi12. These antibodies were surprisingly found to retain verystrong neutralisation of the live SARS-CoV-2 variant strains Victoria,Alpha, Beta, Gamma, Delta and Omicron (e.g. an IC50 of ≤0.01 μg/mlagainst all live strains tested).

The antibody in Table 3 may be selected from the group consisting of:Omi02, Omi03, Omi12, Omi18, Omi28, Omi39 and Omi42. These antibodieswere surprisingly found to retain very strong neutralisation of the liveSARS-CoV-2 variant strains Victoria, Alpha, Beta, Gamma, Delta andOmicron.

Accordingly, in one embodiment, the antibody in Table 3 may be Omi03.Omi03 was found to neutralise the live SARS-CoV-2 variant strainsVictoria, Alpha, Beta, Gamma, Delta and Omicron, and the psuedoviralconstructs of Victoria, Omicron BA.1, Omicron BA.1.1, Omicron BA.2 andOmicron BA.3 (see Tables 13 and 14, FIG. 2 ). In one embodiment, anantibody of the invention may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 695, 696 and 697,respectively, and a CDRL1, CDRL2 and CDRL3 having the amino acidsequences specified in SEQ ID NOs: 698, 699 and 700, respectively. Inone embodiment, an antibody of the invention may comprise a heavy chainvariable domain comprising or consisting of an amino acid sequencehaving ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequenceidentity to the heavy chain variable domain of antibody Omi03 (i.e. SEQID NO: 692). In one embodiment, an antibody of the invention maycomprise a light chain variable domain comprising or consisting of anamino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or100% sequence identity to the light chain variable domain of antibodyOmi03 (i.e. SEQ ID NO: 694). In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain and a light chainvariable domain comprising or consisting of an amino acid sequencehaving ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, 100% sequence identityto the heavy chain variable domain and light chain variable domain,respectively, of antibody Omi03 (i.e. SEQ ID NOs: 692 and 694,respectively).

The heavy chain domain of Omi03 is derived from a IGHV3-53 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi03, and not the light chain of Omi03.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 695, 696 and 697,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi03 (i.e. SEQ ID NO: 692). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 692.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi03, and not the heavy chain of Omi03. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 698, 699 and 700,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi03 (i.e. SEQ ID NO: 694). Theantibody may comprise a light chain variable domain comprising orconsisting of SEQ ID NO: 694.

In one embodiment, the antibody in Table 3 may be Omi12. Omi12 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 735, 736 and 737, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:738, 739 and 740, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi12 (i.e. SEQ ID NO: 732). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi12 (i.e. SEQ ID NO: 734). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi12(i.e. SEQ ID NOs: 732 and 734, respectively).

The heavy chain domain of Omi12 is derived from a IGHV1-58 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi12, and not the light chain of Omi12.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 735, 736 and 737,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi12 (i.e. SEQ ID NO: 732). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 732.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi12, and not the heavy chain of Omi12. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 738, 739 and 740,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi12 (i.e. SEQ ID NO: 734). Theantibody may comprise a light chain variable domain comprising orconsisting of SEQ ID NO: 734.

In one embodiment, the antibody in Table 3 may be Omi02. Omi02 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 685, 686 and 687, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:688, 689 and 690, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi02 (i.e. SEQ ID NO: 682). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi02 (i.e. SEQ ID NO: 684). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi02(i.e. SEQ ID NOs: 682 and 684, respectively).

The heavy chain domain of Omi02 is derived from a IGHV 1-69 v-region,and the inventors have previously demonstrated that switching of theheavy chains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi02, and not the light chain of Omi02.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 685, 686 and 687,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi02 (i.e. SEQ ID NO: 682). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 682.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi02, and not the heavy chain of Omi02. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 688, 689 and 690,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi02 (i.e. SEQ ID NO: 684). Theantibody may comprise a light chain variable domain comprising orconsisting of SEQ ID NO: 684.

In one embodiment, the antibody in Table 3 may be Omi08. Omi08 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1 Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3(see Tables 13 and 14, FIG. 2 ). In one embodiment, an antibody of theinvention may comprise a CDRH1, CDRH2 and CDRH3 having the amino acidsequences specified in SEQ ID NOs: 715, 716 and 717, respectively, and aCDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQID NOs: 718, 719 and 720, respectively. In one embodiment, an antibodyof the invention may comprise a heavy chain variable domain comprisingor consisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi08 (i.e. SEQ ID NO: 712). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi08 (i.e. SEQ ID NO: 714). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi08(i.e. SEQ ID NOs: 712 and 714, respectively).

In one embodiment, the antibody in Table 3 may be Omi42. Omi42 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 955, 956 and 957, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:958, 959 and 960, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi42 (i.e. SEQ ID NO: 952). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi42 (i.e. SEQ ID NO: 954). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi42(i.e. SEQ ID NOs: 952 and 954, respectively).

The heavy chain domain of Omi42 is derived from a IGHV3-9 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi42, and not the light chain of Omi42.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 955, 956 and 957,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi42 (i.e. SEQ ID NO: 952). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 952.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi42, and not the heavy chain of Omi42. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 958, 959 and 960,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi42 (i.e. SEQ ID NO: 954). Theantibody may comprise a light chain variable domain comprising orconsisting of SEQ ID NO: 954.

In one embodiment, the antibody in Table 3 may be Omi16. Omi16 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and OmicronBA.3 (see Tables 13 and 14, FIG. 2 ). In one embodiment, an antibody ofthe invention may comprise a CDRH1, CDRH2 and CDRH3 having the aminoacid sequences specified in SEQ ID NOs: 745, 746 and 747, respectively,and a CDRL1, CDRL2 and CDRL3 having the amino acid sequences specifiedin SEQ ID NOs: 748, 749 and 750, respectively. In one embodiment, anantibody of the invention may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi16 (i.e. SEQ ID NO: 742). In oneembodiment, an antibody of the invention may comprise a light chainvariable domain comprising or consisting of an amino acid sequencehaving ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequenceidentity to the light chain variable domain of antibody Omi16 (i.e. SEQID NO: 744). In one embodiment, an antibody of the invention maycomprise a heavy chain variable domain and a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chainvariable domain and light chain variable domain, respectively, ofantibody Omi16 (i.e. SEQ ID NOs: 742 and 744, respectively).

The heavy chain domain of Omi16 is derived from a IGHV3-66 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi 16, and not the light chain of Omi16. For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3having the amino acid sequences specified in SEQ ID NOs: 745, 746 and747, respectively. The antibody may comprise a heavy chain variabledomain comprising or consisting of an amino acid sequence having ≥80%,≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to theheavy chain variable domain of antibody Omi16 (i.e. SEQ ID NO: 742). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 742.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi 16, and not the heavy chain of Omi 16.For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 havingthe amino acid sequences specified in SEQ ID NOs: 748, 749 and 750,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi16 (i.e. SEQ ID NO: 744). Theantibody may comprise a light chain variable domain comprising orconsisting of SEQ ID NO: 744.

In one embodiment, the antibody in Table 3 may be Omi 18. Omi 18 wasfound to neutralise the live SARS-CoV-2 variant strains Victoria, Alpha,Beta, Gamma, Delta and Omicron, and the psuedoviral constructs ofVictoria, Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3(see Tables 13 and 14, FIG. 2 ). In one embodiment, an antibody of theinvention may comprise a CDRH1, CDRH2 and CDRH3 having the amino acidsequences specified in SEQ ID NOs: 765, 766 and 767, respectively, and aCDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQID NOs: 768, 769 and 770, respectively. In one embodiment, an antibodyof the invention may comprise a heavy chain variable domain comprisingor consisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi18 (i.e. SEQ ID NO: 762). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi18 (i.e. SEQ ID NO: 764). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi18(i.e. SEQ ID NOs: 762 and 764, respectively).

The heavy chain domain of Omi18 is derived from a IGHV3-53 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi18, and not the light chain of Omi18.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 765, 766 and 767,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi18 (i.e. SEQ ID NO: 762).

The antibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 762.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi 18, and not the heavy chain of Omi 18.For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 havingthe amino acid sequences specified in SEQ ID NOs: 768, 769 and 770,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi18 (i.e. SEQ ID NO: 764). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 764.

In one embodiment, the antibody in Table 3 may be Omi20. Omi20 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 775, 776 and 777, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:778, 779 and 780, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi20 (i.e. SEQ ID NO: 772). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi20 (i.e. SEQ ID NO: 774). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi20(i.e. SEQ ID NOs: 772 and 774, respectively).

The heavy chain domain of Omi20 is derived from a IGHV3-66 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi20, and not the light chain of Omi20.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 775, 776 and 777,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi20 (i.e. SEQ ID NO: 772). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 772.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi20, and not the heavy chain of Omi20. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 778, 779 and 780,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi20 (i.e. SEQ ID NO: 774). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 774.

In one embodiment, the antibody in Table 3 may be Omi23. Omi23 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 785, 786 and 787, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:788, 789 and 790, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi23 (i.e. SEQ ID NO: 782). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi23 (i.e. SEQ ID NO: 784). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi23(i.e. SEQ ID NOs: 782 and 784, respectively).

The heavy chain domain of Omi23 is derived from a IGHV4-31 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi23, and not the light chain of Omi23.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 785, 786 and 787,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi23 (i.e. SEQ ID NO: 782). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 782.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi23, and not the heavy chain of Omi23. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 788, 789 and 790,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi23 (i.e. SEQ ID NO: 784). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 784.

In one embodiment, the antibody in Table 3 may be Omi28. Omi28 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 835, 836 and 837, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:838, 839 and 840, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi28 (i.e. SEQ ID NO: 832). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi28 (i.e. SEQ ID NO: 834). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi28(i.e. SEQ ID NOs: 832 and 834, respectively). The heavy chain domain ofOmi28 is derived from a IGHV3-66 v-region, and the inventors havepreviously demonstrated that switching of the heavy chains and lightchains between antibodies derived from the same v-region results in anantibody that is particularly useful with the invention (explainedfurther below). Hence, an antibody of the invention may comprise theheavy chain of Omi28, and not the light chain of Omi28. For example, theantibody may comprise a CDRH1, CDRH2 and CDRH3 having the amino acidsequences specified in SEQ ID NOs: 835, 836 and 837, respectively. Theantibody may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence 10 identity to the heavy chainvariable domain of antibody Omi28 (i.e. SEQ ID NO: 832). The antibodymay comprise a heavy chain variable domain comprising or consisting ofSEQ ID NO: 832.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi28, and not the heavy chain of Omi28. Forexample, the antibody may

comprise a CDRL1, CDRL2 and CDRL3 having the amino acid sequencesspecified in SEQ ID NOs: 838, 839 and 840, respectively. The antibodymay comprise a light chain variable domain comprising or consisting ofan amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%or 100% sequence identity to the light chain variable domain of antibodyOmi28 (i.e. SEQ ID NO: 834). The antibody may comprise alight chainvariable domain comprising or consisting of SEQ ID NO: 834.

In one embodiment, the antibody in Table 3 may be Omi39. Omi39 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 935, 936 and 937, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:938, 939 and 940, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi39 (i.e. SEQ ID NO: 932). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi39 (i.e. SEQ ID NO: 934). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi39(i.e. SEQ ID NOs: 932 and 934, respectively).

In one embodiment, the antibody in Table 3 may be Omi17. Omi17 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 755, 756 and 757, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:758, 759 and 760, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi17 (i.e. SEQ ID NO: 752). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi17 (i.e. SEQ ID NO: 754).

In one embodiment, an antibody of the invention may comprise a heavychain variable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi17(i.e. SEQ ID NOs: 752 and 754, respectively).

The heavy chain domain of Omi17 is derived from a IGHV3-66 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi17, and not the light chain of Omi17.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 755, 756 and 757,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi17 (i.e. SEQ ID NO: 752). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 752.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi 17, and not the heavy chain of Omi 17.For example, the antibody may comprise a CDRL1, CDRL2 and CDRL3 havingthe amino acid sequences specified in SEQ ID NOs: 758, 759 and 760,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi17 (i.e. SEQ ID NO: 754). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 754.

In one embodiment, the antibody in Table 3 may be Omi29. Omi29 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of VictoriaOmicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 845, 846 and 847, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:848, 849 and 850, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi29 (i.e. SEQ ID NO: 842). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi29 (i.e. SEQ ID NO: 844). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi29(i.e. SEQ ID NOs: 842 and 844, respectively).

The heavy chain domain of Omi29 is derived from a IGHV3-53 v-region, andthe inventors have previously demonstrated that switching of the heavychains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi29, and not the light chain of Omi29.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 845, 846 and 847,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi29 (i.e. SEQ ID NO: 842). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 842.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi29, and not the heavy chain of Omi29. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 848, 849 and 850,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi29 (i.e. SEQ ID NO: 844). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 844.

In one embodiment, the antibody in Table 3 may be Omi36. Omi36 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 915, 916 and 917, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:918, 919 and 920, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi36 (i.e. SEQ ID NO: 912). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi36 (i.e. SEQ ID NO: 914).

In one embodiment, an antibody of the invention may comprise a heavychain variable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi36(i.e. SEQ ID NOs: 912 and 914, respectively). The heavy chain domain ofOmi36 is derived from a IGHV3-66 v-region, and the inventors havepreviously demonstrated that switching of the heavy chains and lightchains between antibodies derived from the same v-region results in anantibody that is particularly useful with the invention (explainedfurther below). Hence, an antibody of the invention may comprise theheavy chain of Omi36, and not the light chain of Omi36. For example, theantibody may comprise a CDRH1, CDRH2 and CDRH3 having the amino acidsequences specified in SEQ ID NOs: 915, 916 and 917, respectively. Theantibody may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi36 (i.e. SEQ ID NO: 912). The antibody maycomprise a heavy chain variable domain comprising or consisting of SEQID NO: 912.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi36, and not the heavy chain of Omi36. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 918, 919 and 920,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi36 (i.e. SEQ ID NO: 914). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 914.

In one embodiment, the antibody in Table 3 may be Omi38. Omi38 was foundto neutralise the live SARS-CoV-2 variant strains Victoria, Alpha, Beta,Gamma, Delta and Omicron, and the psuedoviral constructs of Victoria,Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3 (see Tables13 and 14, FIG. 2 ). In one embodiment, an antibody of the invention maycomprise a CDRH1, CDRH2 and CDRH3 having the amino acid sequencesspecified in SEQ ID NOs: 925, 926 and 927, respectively, and a CDRL1,CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOs:928, 929 and 930, respectively. In one embodiment, an antibody of theinvention may comprise a heavy chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99% or 100% sequence identity to the heavy chain variabledomain of antibody Omi38 (i.e. SEQ ID NO: 922). In one embodiment, anantibody of the invention may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Omi38 (i.e. SEQ ID NO: 924). In oneembodiment, an antibody of the invention may comprise a heavy chainvariable domain and a light chain variable domain comprising orconsisting of an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%,≥97%, ≥98%, ≥99%, 100% sequence identity to the heavy chain variabledomain and light chain variable domain, respectively, of antibody Omi38(i.e. SEQ ID NOs: 922 and 924, respectively).

The heavy chain domain of Omi38 is derived from a IGHV 1-69 v-region,and the inventors have previously demonstrated that switching of theheavy chains and light chains between antibodies derived from the samev-region results in an antibody that is particularly useful with theinvention (explained further below). Hence, an antibody of the inventionmay comprise the heavy chain of Omi38, and not the light chain of Omi38.For example, the antibody may comprise a CDRH1, CDRH2 and CDRH3 havingthe amino acid sequences specified in SEQ ID NOs: 925, 926 and 927,respectively. The antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of antibody Omi38 (i.e. SEQ ID NO: 922). Theantibody may comprise a heavy chain variable domain comprising orconsisting of SEQ ID NO: 922.

Alternatively, in an embodiment of the invention, the antibody maycomprise the light chain of Omi38, and not the heavy chain of Omi38. Forexample, the antibody may comprise a CDRL1, CDRL2 and CDRL3 having theamino acid sequences specified in SEQ ID NOs: 928, 929 and 930,respectively. The antibody may comprise a light chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the lightchain variable domain of antibody Om38 (i.e. SEQ ID NO: 924). Theantibody may comprise alight chain variable domain comprising orconsisting of SEQ ID NO: 924.

Mixed Chain Antibodies of the Invention

An antibody of the invention may comprise a light chain variable domaincomprising CDRL1, CDRL2 and CDRL3 from a first antibody in Table 1, 2 or3 and a heavy chain variable domain comprising CDRH1, CDRH2 and CDRH3from a second antibody in Table 1, 2 or 3, with the proviso that thefirst and second antibodies are different. Such antibodies are referredto as mixed chain antibodies herein.

Examples of the mixed chain antibodies useful with the invention areprovided in Tables 4 to 12. Table 4 shows examples of mixed chainantibodies generated from antibodies in Tables 1 to 3 that are derivedfrom the same germline heavy chain IGHV 3-53. Table 5 shows examples ofmixed chain antibodies generated from antibodies in Tables 1 to 3 thatare derived from the same germline heavy chain IGHV 3-53 and IGHV3-66.Table 6 shows examples of mixed chain antibodies generated fromantibodies in Tables 1 to 3 that are derived from the same germlineheavy chain IGHV1-58. Table 7 shows examples of mixed chain antibodiesgenerated from antibodies in Tables 2 and 3 that are derived from thesame germline heavy chain IGHV1-69. Table 8 shows examples of mixedchain antibodies generated from antibodies in Tables 1 to 3 that arederived from the same germline heavy chain IGHV3-30. Table 9 showsexamples of mixed chain antibodies generated from antibodies in Tables 2and 3 that are derived from the same germline heavy chain IGHV3-33.Table 10 shows examples of mixed chain antibodies generated fromantibodies in Tables 1 to 3 that are derived from the same germlineheavy chain IGHV 1-18. Table 11 shows examples of mixed chain antibodiesgenerated from antibodies in Tables 1 and 3 that are derived from thesame germline heavy chain IGHV3-9. Table 12 shows examples of mixedchain antibodies generated from antibodies in Tables 2 and 3 that arederived from the same germline heavy chain IGHV4-31. Examples of mixedchain antibodies that are derived from the same germline heavy chainIGHV1-69 are Omi02H/Beta-49L and Omi38H/Omi24L.

Hence, in one embodiment, an antibody of the invention comprises a heavychain variable domain comprising CDRH1, CDRH2 and CDRH3 from a firstantibody in Table 1, 2 or 3 and a light chain variable domain comprisingCDRL1, CDRL2 and CDRL3 from a second antibody in Table 1, 2 or 3, withthe proviso that the first and second antibodies are different. Theantibody may comprise a heavy chain variable domain amino acid sequencehaving at least 80% sequence identity to the heavy chain variable domainfrom a first antibody in Table 1, 2 or 3, and a light chain variabledomain amino acid sequence having at least 80% sequence identity to thelight chain variable domain from a second antibody in Table 1, 2 or 3,with the proviso that the first and second antibodies are different. Forexample, the antibody may comprise a heavy chain variable domaincomprising or consisting of an amino acid sequence having ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to the heavychain variable domain of an antibody in Table 1, 2 or 3, and a lightchain variable domain comprising or consisting of an amino acid sequencehaving ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequenceidentity to the light chain variable domain of an antibody in Table 1, 2or 3, with the proviso that the first and second antibodies aredifferent.

The first antibody may be in Table 3 and the second antibody may be inTable 3.

The first antibody may be in Table 3 and the second antibody may be inTable 1. The first antibody may be in Table 3 and the second antibodymay be in Table 2. The first antibody may be in Table 1 and the secondantibody may be in Table 3. The first antibody may be in Table 2 and thesecond antibody may be in Table 3. The first antibody may be in Table 1and the second antibody may be in Table 2. The first antibody may be inTable 2 and the second antibody may be in Table 1. The first antibodymay be in Table 2 and the second antibody may be in Table 2. The firstantibody may be in Table 1 and the second antibody may be in Table 1.

In one embodiment, at least one of the first and second antibodies is anantibody from Table 3.

In one embodiment, the first and second antibodies are not both inTable 1. In one embodiment, the first and second antibodies are not bothin Table 2. In one embodiment, the first and second antibodies are notboth selected from an antibody in Table 1 or 2.

In one embodiment, at least one of the heavy chain variable domain andthe light chain variable domain are from Table 3.

The antibody in Table 3 may be selected from the group consisting of:Omi02, Omi03, Omi12, Omi18, Omi28, Omi39 and Omi42. The antibody inTable 3 may be selected from the group consisting of: Omi03, Omi12,Omi02, Omi39, Omi42, Omi16, Omi18, Omi20, Omi 23, Omi28, Omi08, Omi17,Omi29, Omi36 and Omi38. For example, the antibody in Table 3 may beselected from the group consisting of Omi03, Omi12, Omi02, Omi39, Omi42,Omi16, Omi18, Omi20, Omi 23, Omi28 and Omi08. The antibody in Table 3may be selected from the group consisting of Omi03, Omi12, Omi02, Omi39,and Omi42. The antibody in Table 3 may be selected from the groupconsisting of Omi03 and Omi12.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Omi03, Omi18, Omi29, Beta-27,antibody 150, antibody 158, antibody 175, antibody 222 and antibody 269.The heavy chain variable domain of these antibodies are derived fromIGHV3-53. The resulting mixed chain antibodies are set out in Table 4.Hence, the antibody of the invention may comprise all six CDRs (CDRH1-3and CDRL1-3), and/or a heavy chain variable domain and a light chainvariable domain, each comprising or consisting of an amino acid sequencehaving at least 80% sequence identity to the corresponding variabledomain of any one of the mixed chain antibodies as set out in Table 4.

Antibodies derived from IGHV3-53 may be used to produce mixed-chainantibodies with antibodies from IGHV3-66 (e.g. antibodies 40 and 398 inTable 1) (see, e.g. Dejnirattisai, Wanwisa, et al. “The antigenicanatomy of SARS-CoV-2 receptor binding domain.” Cell 184(8) (2021):2183-2200; Supasa, Piyada, et al. “Reduced neutralization of SARS-CoV-2B.1.1.7 variant by convalescent and vaccine sera.” Cell 184(8) (2021):2201-2211; Zhou, Daming, et al. “Evidence of escape of SARS-CoV-2variant B.1.351 from natural and vaccine-induced sera.” Cell 184(9)(2021): 2348-2361; Dejnirattisai, Wanwisa, et al. “Antibody evasion bythe P.1 strain of SARS-CoV-2.” Cell 184(11) (2021): 2939-2954; Liu,Chang, et al. “Reduced neutralization of SARS-CoV-2 B.1.617 by vaccineand convalescent serum.” Cell 184(16) (2021): 4220-4236)). Accordingly,in one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Omi03, Omi18, Omi29, Omi16,Omi17, Omi20, Omi27, Omi36, Beta-27, antibody 150, antibody 158,antibody 175, antibody 222, antibody 269, antibody 40 and antibody 398.The heavy chain variable domain of these antibodies are derived fromIGHV3-53 and IGVH3-66. The resulting mixed chain antibodies are set outin Table 5. Hence, the antibody of the invention may comprise all sixCDRs (CDRH1-3 and CDRL1-3), and/or a heavy chain variable domain and alight chain variable domain, each comprising or consisting of an aminoacid sequence having at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%,≥98%, ≥99% or 100%) sequence identity to the corresponding variabledomain of any one of the mixed chain antibodies as set out in Table 5.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Omi12, Beta-47, Beta-25, antibody55, antibody 165, antibody 253 and antibody 318. The heavy chainvariable domain of these antibodies are derived from IGHV 1-58. Theresulting mixed chain antibodies are set out in Table 6. Hence, theantibody of the invention may comprise all six CDRs (CDRH1-3 andCDRL1-3), and/or a heavy chain variable domain and a light chainvariable domain, each comprising or consisting of an amino acid sequencehaving at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or100%) sequence identity to the corresponding variable domain of any oneof the mixed chain antibodies as set out in Table 6.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Beta-49, Beta-50, Omi02, Omi24,Omi30, Omi31, Omi34 and Omi38. The heavy chain variable domain of theseantibodies are derived from IGHV 1-69. The resulting mixed chainantibodies are set out in Table 7. Hence, the antibody of the inventionmay comprise all six CDRs (CDRH1-3 and CDRL1-3), and/or a heavy chainvariable domain and a light chain variable domain, each comprising orconsisting of an amino acid sequence having at least 80% (e.g. ≥80%,≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100%) sequence identity to thecorresponding variable domain of any one of the mixed chain antibodiesas set out in Table 7.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Beta-22, Beta-29, antibody 159,and Omi09. The heavy chain variable domain of these antibodies arederived from IGHV 3-30. The resulting mixed chain antibodies are set outin Table 8. Hence, the antibody of the invention may comprise all sixCDRs (CDRH1-3 and CDRL1-3), and/or a heavy chain variable domain and alight chain variable domain, each comprising or consisting of an aminoacid sequence having at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%,≥98%, ≥99% or 100%) sequence identity to the corresponding variabledomain of any one of the mixed chain antibodies as set out in Table 8.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Beta-20, Beta-43, Omi32 andOmi33. The heavy chain variable domain of these antibodies are derivedfrom IGHV 3-33. The resulting mixed chain antibodies are set out inTable 9. Hence, the antibody of the invention may comprise all six CDRs(CDRH1-3 and CDRL1-3), and/or a heavy chain variable domain and alightchain variable domain, each comprising or consisting of an amino acidsequence having at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%,≥99% or 100%) sequence identity to the corresponding variable domain ofany one of the mixed chain antibodies as set out in Table 9. The CDRL1-3of Omi32 and Omi33 are identical, meaning that they are, effectively,already exemplary mixed-chain antibodies of the invention.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: antibody 278, Beta-44, Omi26 andOmi41. The heavy chain variable domain of these antibodies are derivedfrom IGHV 1-18. The resulting mixed chain antibodies are set out inTable 10. Hence, the antibody of the invention may comprise all six CDRs(CDRH1-3 and CDRL1-3), and/or a heavy chain variable domain and a lightchain variable domain, each comprising or consisting of an amino acidsequence having at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%,≥99% or 100%) sequence identity to the corresponding variable domain ofany one of the mixed chain antibodies as set out in Table 10.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: antibody 58, Omi25, Omi35 andOmi42. The heavy chain variable domain of these antibodies are derivedfrom IGHV 3-9. The resulting mixed chain antibodies are set out in Table11. Hence, the antibody of the invention may comprise all six CDRs(CDRH1-3 and CDRL1-3), and/or a heavy chain variable domain and a lightchain variable domain, each comprising or consisting of an amino acidsequence having at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%,≥99% or 100%) sequence identity to the corresponding variable domain ofany one of the mixed chain antibodies as set out in Table 11.

In one embodiment, the first antibody and the second antibody are bothselected from the group consisting of: Beta-56 and Omi23. The heavychain variable domain of these antibodies are derived from IGHV 4-31.The resulting mixed chain antibodies are set out in Table 12. Hence, theantibody of the invention may comprise all six CDRs (CDRH1-3 andCDRL1-3), and/or a heavy chain variable domain and a light chainvariable domain, each comprising or consisting of an amino acid sequencehaving at least 80% (e.g. ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or100%) sequence identity to the corresponding variable domain of any oneof the mixed chain antibodies as set out in Table 12.

The constant region domains of an antibody molecule of the invention, ifpresent, may be selected having regard to the proposed function of theantibody molecule, and in particular the effector functions which may berequired. For example, the constant region domains may be human IgA,IgD, IgE, IgG or IgM domains. Typically, the constant regions are ofhuman origin. In particular, human IgG (i.e. IgG1, IgG2, IgG3 or IgG4)constant region domains may be used. Typically, the constant region is ahuman IgG1 constant region.

Certain Antibodies of the Invention

The invention also provides an antibody which is a full length antibodyof any one of the antibodies in Tables 3, 4, 5, 6, 7, 8, 9, 10, 11 or12. In other words, an antibody of the invention comprises a heavy chainvariable domain and a light chain variable domain consisting of theheavy chain variable domain and light chain variable domain,respectively, of any one of the antibodies in Tables 3, 4, 5, 6, 7, 8,9, 10, 11 or 12, and a IgG (e.g. IgG1) constant region.

For example, the antibody of the invention may be a full length Omi02,Omi03, Omi12, Omi18, Omi28, Omi39 or Omi42 antibody. The antibody of theinvention may be a full length Omi03, Omi12, Omi02, Omi39, Omi42, Omi16, Omi18, Omi20, Omi 23, Omi28, Omi08, Omi 17, Omi29, Omi36 or Omi38antibody. These antibodies are all highly potent neutralising mAbs thathave been shown to neutralise the Omicron variant of SARS-CoV-2 with anIC₅₀ of ≤0.1 μg/ml. The antibodies also retain neutralisation of interalia at least the Victoria, Alpha, Beta, Gamma and Delta strains ofSARS-CoV-2 with an IC₅₀ of ≤0.1 μg/ml.

The antibody may be derived from germline heavy chain IGHV1-58 andcomprises proline at position 53 in the heavy chain variable region(according to absolute numbering). For example, the antibody maycomprise a heavy chain variable domain comprising or consisting of anamino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or100% sequence identity to the heavy chain variable domain of Omi-12 (SEQID NO: 731), Beta-47 (SEQ ID NO: 591), Beta-25 (SEQ ID NO: 461),antibody 55 (SEQ ID NO: 62), antibody 165 (SEQ ID NO: 182), antibody 253(SEQ ID NO: 262), or antibody 318 (SEQ ID NO: 332), with the provisothat the amino acid at position 53 in the heavy chain variable region isproline (according to absolute numbering). For example, the antibody maycomprise the heavy chain variable region and the light chain variableregion of Beta-47 (SEQ ID NOs: 591 and 592, respectively), Beta-25 (SEQID NOs: 461 and 462, respectively), antibody 55 (SEQ ID NOs: 62 and 61,respectively), antibody 165 (SEQ ID NO: 182 and 181, respectively),antibody 253 (SEQ ID NOs: 262 and 261, respectively), or antibody 318(SEQ ID NOs: 332 and 331, respectively), except with a V53P mutation inthe heavy chain variable region. The inventors found that suchantibodies are particularly effective against Omicron strains (e.g. seeExample 5).

The position 53 in the heavy chain variable region of theIGHV1-58-derived antibodies Omi-12, Beta-47, Beta-25, antibody 55,antibody 165, antibody 253, and antibody 318 corresponds to position 58according to IMGT numbering.

Accordingly, the invention also provides an antibody derived fromgermline heavy chain IGHV1-58, capable of binding to the spike proteinof coronavirus SARS-CoV-2, wherein the amino acid at position 58 in theheavy chain variable region according to IMGT numbering is proline or issubstituted with proline.

The antibody may comprise a heavy chain variable domain comprising anamino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or100% sequence identity to the heavy chain variable domain of an antibodyderived from germline heavy chain IGHV 1-58, with the proviso that theamino acid at position 58 according to IMGT numbering is proline or issubstituted with proline.

The antibody derived from germline heavy chain IGHV1-58 may be AZD8895,Omi-12, Beta-47, Beta-25, antibody 55, antibody 165, antibody 253, orantibody 318. The amino acid sequence of the heavy chain variable domainof Omi-12, Beta-47, Beta-25, antibody 55, antibody 165, antibody 253, orantibody 318 is described herein (e.g. see Tables 1 to 3). The aminoacid sequence of the heavy chain variable domain of antibody AZD8895 isprovided in SEQ ID NO: 963.

The IGHV1-58 germline V-gene sequence encodes the amino acid sequence:

(SEQ ID NO: 961) MQLVQSGPEVKKPGTSVKVSCKASGFTFTSSAVQWVRQARGQRLEWIGWIVVGSGNTNYAQKFQERVTITRDMSTSTAYMELSSLRSEDTAVYYCAA.Hence, the invention also provides an antibody capable of binding to thespike protein of coronavirus SARS-CoV-2 comprising a heavy chainvariable domain comprising an amino acid sequence having ≥60%, ≥70%,≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity toSEQ ID NO: 961, with the proviso that the amino acid at position 58according to IMGT numbering is proline or is substituted with proline.

The antibody may comprise a heavy chain variable domain comprising anamino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or100% sequence identity to SEQ ID NO: 731, 591, 461, 62, 182, 262, 332 or963, with the proviso that the amino acid at position 58 according toIMGT numbering is proline or is substituted with proline. The antibodymay comprise a heavy chain variable domain comprising an amino acidsequence having SEQ ID NO: 591 461, 62, 182, 262, or 332, wherein thevaline at position 58 according to IMGT numbering is substituted withproline.

The antibody may comprise a heavy chain variable domain comprising anamino acid sequence having SEQ ID NO: 963, wherein the isoleucine atposition 58 according to IMGT numbering is substituted with proline.

In some embodiments, the antibody derived from germline heavy chainIGHV1-58, comprises a light chain variable domain derived from IGLVKappa 3-20. The antibody may comprise a light chain variable domaincomprising an amino acid sequence having ≥80%, ≥90%, ≥95%, ≥96%, ≥97%,≥98%, ≥99% or 100% sequence identity to the light chain variable domainof an antibody derived from germline IGLV Kappa 3-20. The germline IGLVKappa 3-20V sequence may encode the amino acid sequence:EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSP (SEQ ID NO: 967). Hence, theantibody derived from germline heavy chain IGHV 1-58 may comprise alight chain variable domain comprising an amino acid sequence having≥60%, ≥70%, ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequenceidentity to SEQ ID NO: 967.

The invention also provides an antibody capable of binding to the spikeprotein of coronavirus SARS-CoV-2 comprising a heavy chain variabledomain comprising an amino acid sequence that is a modified version ofSEQ ID NO: 961, with the proviso that the amino acid at position 58according to IMGT numbering is proline or is substituted with proline.The modified version of SEQ ID NO: 961 may comprise a modification asdescribed herein, e.g. a substitution, deletion and/or addition. Forexample, the modification may comprise ≤50, ≤45, ≤40, ≤35, ≤30, ≤25,≤20, ≤15, ≤10, ≤9, ≤8, ≤7, ≤6, ≤5, ≤4, ≤3, ≤2 or 1 amino acidsubstitutions and/or deletions from SEQ ID NO: 961. The modification maycomprise ≤4, ≤3, ≤2, or 1 amino acid substitutions and/or deletions fromSEQ ID NO: 961.

The antibody may comprise a heavy chain variable domain comprising anamino acid sequence that is a modified version of SEQ ID NO: 731, 591,461, 62, 182, 262, 332 or 963 which comprises ≤10, ≤9, ≤8, ≤7, ≤6, ≤5,≤4, ≤3, ≤2, or 1 modifications, with the proviso that the amino acid atposition 58 according to IMGT numbering is proline or is substitutedwith proline. The modified version of SEQ ID NO: 731, 591, 461, 62, 182,262, 332 or 963 may comprise a modification as described herein, e.g. asubstitution, deletion and/or addition.

The antibody may comprise a IgG (e.g. IgG1) constant region.

The invention also provides a method of preparing such antibodies. Forexample, the method may comprise modifying an antibody derived from thegermline heavy chain IGHV1-58, capable of binding to the spike proteinof coronavirus SARS-CoV-2, by substituting the amino acid at position 58in the heavy chain variable region (according to IMGT numbering) withproline. The antibody derived from the germline heavy chain IGHV1-58 maybe AZD8895, Omi-12, Beta-47, Beta-25, antibody 55, antibody 165,antibody 253, or antibody 318. The amino acid sequence of the heavychain variable domain of each these antibodies is described herein (e.g.see Tables 1 to 3 and SEQ ID NO: 963). The invention also provides anantibody obtainable or obtained by the method.

Properties of the Antibodies of the Invention

An antibody of the invention may be or may comprise a modification fromthe amino acid sequence of an antibody in Tables 1 to 12, whilstmaintaining the activity and/or function of the antibody. Themodification may a substitution, deletion and/or addition. For example,the modification may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to30 or more amino acid substitutions and/or deletions from the amino acidsequence of an antibody in Tables 1 to 12. For example, the modificationmay comprise an amino acid substituted with an alternative amino acidhaving similar properties. Some properties of the 20 main amino acids,which can be used to select suitable substituents are as follows:

Ala aliphatic, hydrophobic, neutral Met hydrophobic, neutral Cys polar,hydrophobic, neutral Asn polar, hydrophilic, neutral Asp polar,hydrophilic, charged (−) Pro hydrophobic, neutral Glu polar,hydrophilic, charged (−) Gln polar, hydrophilic, neutral Phe aromatic,hydrophobic, neutral Arg polar, hydrophilic, charged (+) Gly aliphatic,neutral Ser polar, hydrophilic, neutral His aromatic, polar,hydrophilic, Thr polar, hydrophilic, neutral charged (+) Ile aliphatic,hydrophobic, neutral Val aliphatic, hydrophobic, neutral Lys polar,hydrophilic, charged (+) Trp aromatic, hydrophobic, neutral Leualiphatic, hydrophobic, neutral Tyr aromatic, polar, hydrophobic

The modification may comprise a derivatised amino acid, e.g. a labelledor non-natural amino acid, providing the function of the antibody is notsignificantly adversely affected.

Modification of antibodies of the invention as described above may beprepared during synthesis of the antibody or by post-productionmodification, or when the antibody is in recombinant form using theknown techniques of site-directed mutagenesis, random mutagenesis, orenzymatic cleavage and/or ligation of nucleic acids.

Antibodies of the invention may be modified (e.g. as described above) toimprove the potency of said antibodies or to adapt said antibodies tonew SARS-CoV-2 variants. The modifications may be amino acidsubstitutions to adapt the antibody to substitutions in a virus variant.For example, the known mode of binding of an antibody to the spikeprotein (e.g. by crystal structure determination, or modelling) may beused to identify the amino acids of the antibody that interact with thesubstitution in the virus variant. This information can then be used toidentify possible substitutions of the antibody that will compensate forthe change in the epitope characteristics. For example, a substitutionof a hydrophobic amino acid in the spike protein to a negatively changesamino acid may be compensated by substituting the amino acid from theantibody that interacts with said amino acid in the spike protein to apositively charged amino acid. Methods for identifying residues of anantibody that may be substituted are encompassed by the presentdisclosure, for example, by determining the structure ofantibody-antigen complexes as described herein.

The antibodies of the invention may contain one or more modifications toincrease their cross-lineage neutralisation property. For example, E484of the spike protein, which is a key residue that mediates theinteraction with ACE2, is mutated in some SARS-CoV-2 strains (e.g.Victoria strain which contains E484, but P.1 and B.1.351 strains containE484K) resulting in differing neutralisation effects of the antibodies.Thus, antibodies that bind to E484 can be modified to compensate for thechanges in E484 of the spike protein. For example, E484 is mutated froma positively charge to negatively charged amino acid in SAR-CoV-2strains of B.1.351 or P.1 lineage, when compared to the original strain.The amino acid residues of antibodies that bind to or near E484 may bemutated to compensate for the change in charge. Examples of such aminoacid residues may be G104 and/or K108 in SEQ ID NO: 102 of antibody 88,or R52 in SEQ ID NO: 372 of antibody 384.

Antibodies of the invention may be isolated antibodies. An isolatedantibody is an antibody which is substantially free of other antibodieshaving different antigenic specificities.

The term ‘antibody’ as used herein may relate to whole antibodies (i.e.comprising the elements of two heavy chains and two light chainsinter-connected by disulphide bonds) as well as antigen-bindingfragments thereof. Antibodies typically comprise immunologically activeportions of immunoglobulin (Ig) molecules, i.e., molecules that containan antigen binding site that specifically binds (immunoreacts with) anantigen. By “specifically binds” or “immunoreacts with” is meant thatthe antibody reacts with one or more antigenic determinants of thedesired antigen and does not react with other polypeptides. Each heavychain is comprised of a heavy chain variable region (abbreviated hereinas HCVR or VH) and at least one heavy chain constant region. Each lightchain is comprised of a light chain variable region (abbreviated hereinas LCVR or VL) and a light chain constant region. The variable regionsof the heavy and light chains contain a binding domain that interactswith an antigen. The VH and VL regions can be further subdivided intoregions of hypervariability, termed complementarity determining regions(CDR), interspersed with regions that are more conserved, termedframework regions (FR).

Antibodies may include, but are not limited to, polyclonal, monoclonal,chimeric, dAb (domain antibody), single chain, Fab, Fab′ and F(ab′)2fragments, scFvs, and Fab expression libraries An antibody of theinvention may be a monoclonal antibody. Monoclonal antibodies (mAbs) ofthe invention may be produced by a variety of techniques, includingconventional monoclonal antibody methodology, for example thosedisclosed in “Monoclonal Antibodies: a manual of techniques” (Zola H,1987, CRC Press) and in “Monoclonal Hybridoma Antibodies: techniques andapplications” (Hurrell J G R, 1982 CRC Press). An antibody of theinvention may be multispecific, such as bispecific. A bispecificantibody of the invention binds two different epitopes. The epitopes maybe in the same protein (e.g. two epitopes in spike protein ofSARS-CoV-2) or different proteins (e.g. one epitope in spike protein andone epitope in another protein (such as coat protein) of SARS-CoV-2).

In one embodiment, a bispecific antibody of the invention may bind totwo separate epitopes on the spike protein of SARS-CoV-2. The bispecificantibody may bind to the NTD of the spike protein and to the RBD of thespike protein. The bispecific antibody may bind to two differentepitopes in the RBD of the spike protein.

One or more (e.g. two) antibodies of the invention can be coupled toform a multispecific (e.g. bispecific) antibody. Methods to preparemultispecific, e.g. bispecific, antibodies are well known in the art.

An antibody may be selected from the group consisting of single chainantibodies, single chain variable fragments (scFvs), variable fragments(Fvs), fragment antigen-binding regions (Fabs), recombinant antibodies,monoclonal antibodies, fusion proteins comprising the antigen-bindingdomain of a native antibody or an aptamer, single-domain antibodies(sdAbs), also known as VHH antibodies, nanobodies (Camelid-derivedsingle-domain antibodies), shark IgNAR-derived single-domain antibodyfragments called VNAR, diabodies, triabodies, Anticalins, aptamers (DNAor RNA) and active components or fragments thereof.

The constant region domains of an antibody molecule of the invention, ifpresent, may be selected having regard to the proposed function of theantibody molecule, and in particular the effector functions which may berequired. For example, the constant region domains may be human IgA,IgD, IgE, IgG or IgM domains. Typically, the constant regions are ofhuman origin. In particular, human IgG (i.e. IgG1, IgG2, IgG3 or IgG4)constant region domains may be used. Typically, the constant region is ahuman IgG1 constant region.

The light chain constant region may be either lambda or kappa.

Antibodies of the invention may be mono-specific or multi-specific (e.g.bi-specific). A multi-specific antibody comprises at least two differentvariable domains, wherein each variable domain is capable of binding toa separate antigen or to a different epitope on the same antigen.

An antibody of the invention may be a chimeric antibody, a CDR-graftedantibody, a nanobody, a human or humanised antibody. Typically, theantibody is a human antibody.

Fully human antibodies are those antibodies in which the variableregions and the constant regions (where present) of both the heavy andthe light chains are all of human origin, or substantially identical tosequences of human origin, but not necessarily from the same antibody.

The antibody of the invention may be a full-length antibody.

The antibody of the invention may be an antigen-binding fragment. Anantigen-binding fragment of the invention binds to the same epitope ofthe parent antibody, i.e. the antibody from which the antigen-bindingfragment is derived. An antigen-binding fragment of the inventiontypically retains the parts of the parent antibody that interact withthe epitope. The antigen-binding fragment typically comprise thecomplementarity-determining regions (CDRs) that interact with theantigen, such as one, two, three, four, five or six CDRs. In someembodiments, the antigen-binding fragment further comprises thestructural scaffold surrounding the CDRs of the parent antibody, such asthe variable region domains of the heavy and/or light chains. Typically,the antigen-binding fragment retains the same or similar bindingaffinity to the antigen as the parent antibody.

An antigen-binding fragment does not necessarily have an identicalsequence to the parent antibody. In one embodiment, the antigen-bindingfragment may have ≥70%, ≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99%, 100%sequence identity with the respective CDRs of the parent antibody. Inone embodiment, the antigen-binding fragment may have ≥70%, ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99%, 100% sequence identity with the respectivevariable region domains of the parent antibody. Typically, thenon-identical amino acids of a variable region are not in the CDRs.

The antigen-binding fragments of antibodies of the invention retain theability to selectively bind to an antigen. Antigen-binding fragments ofantibodies include single chain antibodies (i.e. a full-length heavychain and light chain); Fab, modified Fab, Fab′, modified Fab′, F(ab′)2,Fv, Fab-Fv, Fab-dsFv, single domain antibodies (e.g. VH or VL or VHH),scFv.

An antigen-binding function of an antibody can be performed by fragmentsof a full-length antibody. The methods for creating and manufacturingthese antibody fragments are well known in the art (see for exampleVerma R et al., 1998, J. Immunol. Methods, 216, 165-181).

Methods for screening antibodies of the invention that do not share 100%amino acid sequence identity with one of the antibodies disclosedherein, that possess the desired specificity, affinity and functionalactivity include the methods described herein, e.g. enzyme linkedimmunosorbent assays, biacore, focus reduction neutralisation assay(FRNT), and other techniques known within the art.

With regards to function, an antibody of the invention may be able toneutralise at least one biological activity of SAR-CoV-2 (a neutralisingantibody), particularly to neutralise virus infectivity.

Neutralisation may also be determined using IC₅₀ or IC₉₀ values. Forexample, the antibody may have an IC₅₀ value of ≤0.1 μg/ml, ≤0.05 μg/ml,≤0.01 μg/ml≤0.005 μg/ml or ≤0.002 μg/ml. In some instances an antibodyof the invention may have an IC₅₀ value of between 0.0001 μg/ml and 0.1μg/ml, sometimes between 0.0001 μg/ml and 0.05 μg/ml or even between0.0001 μg/ml and 0.001 μg/ml.

For example, the IC₅₀ values of some of the antibodies of Tables 1 to 12are provided in Tables 13 to 16.

The ability of an antibody to neutralise virus infectivity may bemeasured using an appropriate assay, particularly using a cell-basedneutralisation assay, as shown in the Examples. For example, theneutralisation ability may be measured in a focus reductionneutralisation assay (FRNT) where the reduction in the number of cells(e.g. human cells) infected with the virus (e.g. for 2 hours at 37° C.)in the presence of the antibody is compared to a negative control inwhich no antibodies were added.

An antibody of the invention may block the interaction between the spikeprotein of SAR-CoV-2 with the cell surface receptor,angiotensin-converting enzyme 2 (ACE2), of the target cell, e.g. bydirect blocking or by disrupting the pre-fusion conformation of thespike protein.

Blocking of the interaction between spike and ACE2 can be total orpartial. For example, an antibody of the invention may reduce spike-ACE2formation by ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, ≥99% or 100%. Blockingof spike-ACE2 formation can be measured by any suitable means known inthe art, for example, by ELISA.

Most antibodies showing neutralisation also showed blocking of theinteraction between the spike protein and ACE2. Furthermore, a number ofnon-neutralising antibodies are good ACE2 blockers.

In terms of binding kinetics, an antibody of the invention may have anaffinity constant (K_(D)) value for the spike protein of SARS-CoV-2 of≤5 nM, ≤4 nM, ≤3 nM, ≤2 nM, ≤InM, ≤0.5 nM, ≤0.4 nM, ≤0.3 nM, ≤0.2 nM or≤0.1 nM.

The KD value can be measured by any suitable means known in the art, forexample, by ELISA or Surface Plasmon Resonance (Biacore) at 25° C.

Binding affinity (K_(D)) may be quantified by determining thedissociation constant (K_(d)) and association constant (K_(a)) for anantibody and its target. For example, the antibody may have anassociation constant (K_(a)) of ≥10000 M⁻¹s⁻¹, ≥50000 M⁻¹s⁻¹, ≥100000M⁻¹s⁻¹, ≥200000 M⁻¹s⁻¹ or ≥500000 M⁻¹s⁻¹, and/or a dissociation constant(K_(d)) of ≤0.001 s⁻¹, ≤0.0005 s⁻¹, ≤0.004 s⁻¹, ≤0.003 s⁻¹, ≤0.002 s⁻¹or ≤0.0001 s⁻¹.

An antibody of the invention is preferably able to provide in vivoprotection in coronavirus (e.g. SARS-CoV-2) infected animals. Forexample, administration of an antibody of the invention to coronavirus(e.g. SARS-CoV-2) infected animals may result in a survival rate of≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95% or 100%.

Survival rates may be determined using routine methods.

Antibodies of the invention may have any combination of one or more ofthe above properties.

Antibodies of the invention may bind to the same epitope as, or competefor binding to SARS-CoV-2 spike protein with, any one of the antibodiesdescribed herein (i.e. in particular with antibodies with the heavy andlight chain variable regions described above). Methods for identifyingantibodies binding to the same epitope, or cross-competing with oneanother, are used in the Examples and discussed further below.

Fc Regions

An antibody of the invention may or may not comprise an Fc domain.

The antibodies of the invention may be modified in the Fc region inorder to improve their stability. Such modifications are known in theart. Modifications may improve the stability of the antibody duringstorage of the antibody. The in vivo half-life of the antibody may beimproved by modifications of the Fc-region. For example, cysteineresidue(s) can be introduced into the Fc region, thereby allowinginterchain disulphide bond formation in this region. The homodimericantibody thus generated can have improved internalization capabilityand/or increased complement-mediated cell killing and antibody-dependentcellular cytotoxicity (ADCC). (See Caron et al., J. Exp Med., 176:1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992)).

Alternatively, an antibody can be engineered that has dual Fc regionsand can thereby have enhanced complement lysis and ADCC capabilities.(See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989)).

For example, an antibody of the invention may be modified to promote theinteraction of the Fc domain with FcRn. The Fc domain may be modified toimprove the stability of the antibody by affecting Fc and FcRninteraction at low pH, such as in the endosome. The M252Y/S254T/T256E(YTE) mutation may be used to improve the half-life of an IgG1 antibody.

The antibody may be modified to affect the interaction of the antibodywith other receptors, such as FcγRI, FcγRIIA, FcγRIIB, FcγRIII, andFcαR. Such modifications may be used to affect the effector functions ofthe antibody.

In one embodiment, an antibody of the invention comprises an altered Fcdomain as described herein below. In another preferred embodiment anantibody of the invention comprises an Fc domain, but the sequence ofthe Fc domain has been altered to modify one or more Fc effectorfunctions.

In one embodiment, an antibody of the invention comprises a “silenced”Fc region. For example, in one embodiment an antibody of the inventiondoes not display the effector function or functions associated with anormal Fc region. An Fc region of an antibody of the invention does notbind to one or more Fc receptors.

In one embodiment, an antibody of the invention does not comprise a CH₂domain. In one embodiment, an antibody of the invention does notcomprise a CH₃ domain. In one embodiment, an antibody of the inventioncomprises additional CH₂ and/or CH₃ domains.

In one embodiment, an antibody of the invention does not bind Fcreceptors. In one embodiment, an antibody of the invention does not bindcomplement. In an alternative embodiment, an antibody of the inventiondoes not bind FcγR, but does bind complement.

In one embodiment, an antibody of the invention in general may comprisemodifications that alter serum half-life of the antibody. Hence, inanother embodiment, an antibody of the invention has Fc regionmodification(s) that alter the half-life of the antibody. Suchmodifications may be present as well as those that alter Fc functions.In one preferred embodiment, an antibody of the invention hasmodification(s) that alter the serum half-life of the antibody.

In one embodiment, an antibody of the invention may comprise a humanconstant region, for instance IgA, IgD, IgE, IgG or IgM domains. Inparticular, human IgG constant region domains may be used, especially ofthe IgG1 and IgG3 isotypes when the antibody molecule is intended fortherapeutic uses where antibody effector functions are required.Alternatively, IgG2 and IgG4 isotypes may be used when the antibodymolecule is intended for therapeutic purposes and antibody effectorfunctions are not required.

In one embodiment, the antibody heavy chain comprises a CH₁ domain andthe antibody light chain comprises a CL domain, either kappa or lambda.In one embodiment, the antibody heavy chain comprises a CH₁ domain, aCH₂ domain and a CH₃ domain and the antibody light chain comprises a CLdomain, either kappa or lambda.

The four human IgG isotypes bind the activating Fcγ receptors (FcγRI,FcγRIIa, FcγRIIc, FcγRIIIa), the inhibitory FcγRIIb receptor, and thefirst component of complement (Clq) with different affinities, yieldingvery different effector functions (Bruhns P. et al., 2009. Specificityand affinity of human Fcγ receptors and their polymorphic variants forhuman IgG subclasses. Blood. 113(16):3716-25), see also Jeffrey B.Stavenhagen, et al. Cancer Research 2007 Sep. 15; 67(18):8882-90. In oneembodiment, an antibody of the invention does not bind to Fc receptors.In another embodiment of the invention, the antibody does bind to one ormore type of Fc receptors.

In one embodiment the Fc region employed is mutated, in particular amutation described herein. In one embodiment the Fc mutation is selectedfrom the group comprising a mutation to remove or enhance binding of theFc region to an Fc receptor, a mutation to increase or remove aneffector function, a mutation to increase or decrease half-life of theantibody and a combination of the same. In one embodiment, wherereference is made to the impact of a modification it may be demonstratedby comparison to the equivalent antibody but lacking the modification.

Some antibodies that selectively bind FcRn at pH 6.0, but not pH 7.4,exhibit a higher half-life in a variety of animal models. Severalmutations located at the interface between the CH₂ and CH₃ domains, suchas T250Q/M428L (Hinton P R. et al., 2004. Engineered human IgGantibodies with longer serum half-lives in primates. J Biol Chem.279(8):6213-6) and M252Y/5254T/T256E+H433K/N434F (Vaccaro C. et al.,2005. Engineering the Fc region of immunoglobulin G to modulate in vivoantibody levels. Nat Biotechnol. 23(10):1283-8), have been shown toincrease the binding affinity to FcRn and the half-life of IgG1 in vivo.Hence, modifications may be present at M252/5254/T256+H44/N434 thatalter serum half-life and in particular M252Y/5254T/T256E+H433K/N434Fmay be present. In one embodiment, it is desired to increase half-life.In another embodiment, it may be actually desired to decrease serumhalf-life of the antibody and so modifications may be present thatdecrease serum half-life.

Numerous mutations have been made in the CH₂ domain of human IgG1 andtheir effect on ADCC and CDC tested in vitro (Idusogie E E. et al.,2001. Engineered antibodies with increased activity to recruitcomplement. J Immunol. 166(4):2571-5). Notably, alanine substitution atposition 333 was reported to increase both ADCC and CDC. Hence, in oneembodiment a modification at position 333 may be present, and inparticular one that alters ability to recruit complement. Lazar et al.described a triple mutant (S239D/I332E/A330L) with a higher affinity forFcγRIIIa and a lower affinity for FcγRIIb resulting in enhanced ADCC(Lazar G A. et al., 2006). Hence, modifications at S239/I332/A330 may bepresent, particularly those that alter affinity for Fc receptors and inparticular S239D/I332E/A330L. Engineered antibody Fc variants withenhanced effector function. PNAS 103(11): 4005-4010). The same mutationswere used to generate an antibody with increased ADCC (Ryan M C. et al.,2007. Antibody targeting of B-cell maturation antigen on malignantplasma cells. Mol. Cancer Ther., 6: 3009-3018). Richards et al. studieda slightly different triple mutant (S239D/I332E/G236A) with improvedFcγRIIIa affinity and FcγRIIa/FcγRIIb ratio that mediates enhancedphagocytosis of target cells by macrophages (Richards J O et al 2008.Optimization of antibody binding to Fcgamma RIIa enhances macrophagephagocytosis of tumor cells. Mol Cancer Ther. 7(8):2517-27). In oneembodiment, S239D/1332E/G236A modifications may be therefore present.

In another embodiment, an antibody of the invention may have a modifiedhinge region and/or CH1 region. Alternatively, the isotype employed maybe chosen as it has a particular hinge regions.

Major Public V Regions

Public V-regions, also described as public V-genes herein, are the Vregions of the germline heavy chain and light chain regions that arefound in a large proportion of the antibody responses to SARS-CoV-2found within the population. In this application, the V regions arespecific responses to the Beta SARS-CoV-2 variant. That is to say, manyindividuals utilise the same v-regions from their germline v-regionrepertoire when generating an immune response to SARS-CoV-2 variants.

As used herein, an antibody “derived” from a specific v-region refers toantibodies that were generated by V(D)J recombination using thatgermline v-region sequence. For example, the germline IGHV3-53 v-regionsequence may undergo somatic recombination and somatic mutation toarrive at an antibody that specifically binds to the spike protein ofSARS-CoV-2. The nucleotide sequence encoding the antibody is unlikely tocomprise a sequence identical to the IGHV3-53 germline sequence,nevertheless, the antibody is still derived from this v-region. Anantibody of the invention typically comprises no more than non-silentmutations in the v-region, when compared to the germline sequence, suchas no more than 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 non-silentmutations. An antibody of the invention typically comprises no between2-20 non-silent mutations in the v-region, when compared to the germlinesequence, such as between 5-15, 6-13 and 7-12 non-silent mutations.Germline v-region sequences are well known in the art, and methods ofidentifying whether a certain region of an antibody is derived from aparticular germline v-region sequence are also well known in the art.

In one embodiment, an antibody of the invention derives from a v-regionselected from IGHV3-53, IGHV1-58, IGHV3-66, IGHV1-69, IGHV3-30,IGHV3-33, IGHV1-18, IGHV13-9 or IGHV4-31. The inventors found that thepotent neutralising antibodies identified herein comprised relativelyfew mutations in the CDRs of these v-regions. Thus, in one embodiment,an antibody of the invention encoded by a v-region selected fromIGHV3-53, IGHV1-58, IGHV3-66, IGHV1-69, IGHV3-30, IGHV3-33, IGHV1-18,IGHV13-9 or IGHV4-31 and having 2-20 non-silent nucleotide mutations, or5-15 non-silent mutations, such as 15 or less, 14 or less, 13 or less,12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6or less, 5 or less, 4 or less 3 or less or 2 non-silent mutations whencompared to the naturally occurring germline sequence. A silent mutationas defined herein is a change in the nucleotide sequence without achange in the amino acid sequence for which the nucleotide sequenceencodes. A non-silent mutation is therefore a mutation that leads to achange in the amino acid sequence encoded by the nucleotide sequence.

The inventors have surprisingly found that the light chain variableregion of two antibodies having the same heavy chain v-region may beexchanged to produce a mixed-chain antibody comprising the heavy chainvariable region of a first antibody and the light chain variable regionof a second antibody. For example, the two antibodies may both comprisea heavy chain variable region derived from IGHV3-53. Preferably, bothantibodies also comprise a light chain variable region derived from thesame light chain v-region, although this is not essential because, forexample, the light chain of antibody 222 may be matched with any heavychain variable region derived from IGHV3-53 and lead to a potentneutralising antibody. As described above, the two antibodies maycomprise a heavy chain variable region derived from IGHV3-53 and/orIGHV3-66.

In one embodiment, an antibody of the invention comprises the CDRs of anheavy chain variable domain of an antibody derived from a major publicv-region selected from IGHV3-53, IGHV1-58, IGHV3-66, IGHV4-39, IGHV3-30,IGHV5-51, IGHV1-02 or IGHV3-33, such as antibodies Omi03, Omi18, Omi29,Beta-27, antibody 150, antibody 158, antibody 175, antibody 222 andantibody 269 for IGHV3-53, antibodies Omi16, Omi17, Omi20, Omi27, Omi36,antibody 40 and antibody 398 for IGHV3-66, antibodies Omi12, Beta-47,Beta-25, antibody 55, antibody 165, antibody 253 for IGHV1-58,antibodies Beta-49, Beta-50, Omi02, Omi24, Omi30, Omi31, Omi34 and Omi38for IGHV1-69, antibodies Beta-22, Beta-29, antibody 159 and Omi09 forIGHV3-30, antibodies Beta-20, Beta-43, Omi32 and Omi 33 for IGHV3-33,antibodies antibody 278, Beta-44, Omi26 and Omi41 for IGHV1-18,antibodies 58, Omi25, Omi35 and Omi42 for IGHV3-9, or antibodies Beta-56and Omi23 for IGHV4-31. The SEQ ID NOs corresponding to the CDRs of eachof these antibodies are shown in Tables 1, 2 and 3.

In one embodiment, an antibody of the invention comprises the heavychain variable domain of an antibody derived from a major publicv-region selected from IGHV3-53, IGHV 1-58, IGHV3-66, IGHV4-39,IGHV3-30, IGHV5-51, IGHV1-02 or IGHV3-33, such as antibodies Omi03,Omi18, Omi29, Beta-27, antibody 150, antibody 158, antibody 175,antibody 222 and antibody 269 for IGHV3-53, antibodies Omi16, Omi17,Omi20, Omi27, Omi36, antibody 40 and antibody 398 for IGHV3-66,antibodies Omi12, Beta-47, Beta-25, antibody 55, antibody 165, antibody253 for IGHV1-58, antibodies Beta-49, Beta-50, Omi02, Omi24, Omi30,Omi31, Omi34 and Omi38 for IGHV1-69, antibodies Beta-22, Beta-29,antibody 159 and Omi09 for IGHV3-30, antibodies Beta-20, Beta-43, Omi32and Omi 33 for IGHV3-33, antibodies antibody 278, Beta-44, Omi26 andOmi41 for IGHV1-18, antibodies 58, Omi25, Omi35 and Omi42 for IGHV3-9,or antibodies Beta-56 and Omi23 for IGHV4-31. The SEQ ID NOscorresponding to the CDRs of each of these antibodies are shown inTables 1, 2 and 3.

In one embodiment, the invention provides a method of generating anantibody that binds specifically to the spike protein of SARS-CoV-2(e.g. a SARS-CoV-2 strain of the Alpha, Beta, Gamma, Delta and/orOmicron lineages), the method comprising identifying two or moreantibodies derived from the same light chain and/or heavy chainv-regions, replacing the light chain of a first antibody with the lightchain of a second antibody, to thereby generate a mixed-chain antibodycomprising the heavy chain of the first antibody and the light chain ofthe second antibody. In one embodiment, the method further comprisesdetermining the affinity for and/or neutralisation of SARS-CoV-2 of themixed-chain antibody. The method may further comprise comparing theaffinity of the mixed-chain antibody with that of the first and/orsecond antibodies. The method may further comprise selecting a mixedchain antibody that has the same or greater affinity than the firstand/or second antibodies. In some embodiments, the heavy chain v-regionis IGHV 1-58 and/or the light chain v-region is IGLV Kappa 3-20.

In another embodiment, the invention provides an antibody thatspecifically binds to the Omicron variant of SARS-CoV-2, wherein theantibody has a v-region derived from IGHV1-69. It has been surprisinglydiscovered that antibody responses to infection with the Omicron variantof SARS-CoV-2 is biased towards antibodies with a heavy chain variableregion derived from IGHV1-69. In one embodiment, wherein the antibodyheavy chain is derived from IGHV1-69, the antibody of the inventioncomprises the CDRH1, CDRH2 and CDRH3 from Beta-49, Beta-50, Omi02,Omi24, Omi30, Omi31, Omi34 and Omi38.

Antibody Conjugates

The invention also pertains to immunoconjugates comprising an antibodyconjugated to a cytotoxic agent such as a toxin (e.g., an enzymaticallyactive toxin of bacterial, fungal, plant, or animal origin, or fragmentsthereof), or a radioactive isotope (i.e., a radioconjugate). Conjugatesof the antibody and cytotoxic agent may be made using a variety ofbifunctional protein-coupling agents known in the art.

An antibody, of the invention may be conjugated to a molecule thatmodulates or alters serum half-life. An antibody, of the invention maybind to albumin, for example in order to modulate the serum half-life.In one embodiment, an antibody of the invention will also include abinding region specific for albumin. In another embodiment, an antibodyof the invention may include a peptide linker which is an albuminbinding peptide. Examples of albumin binding peptides are included inWO2015/197772 and WO2007/106120 the entirety of which are incorporatedby reference.

Polynucleotides, Vectors and Host Cells

The invention also provides one or more isolated polynucleotides (e.g.DNA) encoding the antibody of the invention. In one embodiment, thepolynucleotide sequence is collectively present on more than onepolynucleotide, but collectively together they are able to encode anantibody of the invention. For example, the polynucleotides may encodethe heavy and/or light chain variable regions(s) of an antibody of theinvention. The polynucleotides may encode the full heavy and/or lightchain of an antibody of the invention. Typically, one polynucleotidewould encode each of the heavy and light chains.

Polynucleotides which encode an antibody of the invention can beobtained by methods well known to those skilled in the art. For example,DNA sequences coding for part or all of the antibody heavy and lightchains may be synthesised as desired from the corresponding amino acidsequences. General methods by which the vectors may be constructed,transfection methods and culture methods are well known to those skilledin the art. In this respect, reference is made to “Current Protocols inMolecular Biology”, 1999, F. M. Ausubel (ed), Wiley Interscience, NewYork and the Maniatis Manual produced by Cold Spring Harbor Publishing.A polynucleotide of the invention may be provided in the form of anexpression cassette, which includes control sequences operably linked tothe inserted sequence, thus allowing for expression of the antibody ofthe invention in vivo. Hence, the invention also provides one or moreexpression cassettes encoding the one or more polynucleotides thatencoding an antibody of the invention. These expression cassettes, inturn, are typically provided within vectors (e.g. plasmids orrecombinant viral vectors). Hence, in one embodiment, the inventionprovides a vector encoding an antibody of the invention. In anotherembodiment, the invention provides vectors which collectively encode anantibody of the invention. The vectors may be cloning vectors orexpression vectors. A suitable vector may be any vector which is capableof carrying a sufficient amount of genetic information, and allowingexpression of a polypeptide of the invention. The polynucleotides,expression cassettes or vectors of the invention are introduced into ahost cell, e.g. by transfection. Hence, the invention also provides ahost cell comprising the one or more polynucleotides, expressioncassettes or vectors of the invention. The polynucleotides, expressioncassettes or vectors of the invention may be introduced transiently orpermanently into the host cell, allowing expression of an antibody fromthe one or more polynucleotides, expression cassettes or vectors. Suchhost cells include transient, or preferably stable higher eukaryoticcell lines, such as mammalian cells or insect cells, lower eukaryoticcells, such as yeast, or prokaryotic cells, such as bacteria cells.Particular examples of cells include mammalian HEK293, such as HEK293F,HEK293T, HEK293S or HEK Expi293F, CHO, HeLa, NS0 and COS cells, or anyother cell line used herein, such as the ones used in the Examples.Preferably the cell line selected will be one which is not only stable,but also allows for mature glycosylation.

The invention also provides a process for the production of an antibodyof the invention, comprising culturing a host cell containing one ormore vectors of the invention under conditions suitable for theexpression of the antibody from the one or more polynucleotides of theinvention, and isolating the antibody from said culture.

Combination of Antibodies

The inventors found that certain Table 3 antibodies are particularlyeffective when used in combination, and certain combinations of Table 3,Table 2, and Table 1 antibodies, e.g. to minimise loss of activity dueto SARS-CoV-2 variants, maximise therapeutic effects and/or increasediagnostic power. Useful combinations include the antibodies that do notcross-compete with one another and/or bind to non-overlapping epitopes.

Thus, the invention provides a combination of the antibodies of theinvention, wherein each antibody is capable of binding to the spikeprotein of coronavirus SARS-CoV-2, wherein at least one antibodycomprises at least three CDRs of any one of the 28 antibodies in Table3.

A combination of the antibodies of the invention may be useful as atherapeutic cocktail. Hence, the invention also provides apharmaceutical composition comprising a combination of the antibodies ofthe invention, as explained further below.

A combination of the antibodies of the invention may be useful fordiagnosis. Hence, the invention also provides a diagnostic kitcomprising a combination of the antibodies of the invention. Alsoprovided herein are methods of diagnosing a disease or complicationassociated with coronavirus infections in a subject, as explainedfurther below. A fully cross-neutralising antibody, e.g. Omi03, may beused as a reference to confirm the presence and/or amount of anyvariants of concern (VoC) SARS-CoV-2 in the sample. An antibody thatbinds to a limited number of VoCs may be used to confirm the presenceand/or amount of that VoC in the sample. For example, if Omi03 exhibitsbinding to the sample but Omi24 does not exhibit binding to the sampleof SARS-CoV-2, then the spike protein may be the spike protein of theDelta VoC. This may be determined by any method known to the skilledperson, such as via an immunoassay, e.g. an ELISA or animmunochromatographic assay. Reduced binding may be determined bycomparison and/or normalisation to the reference, and/or by comparisonto positive/negative control samples or data.

Pharmaceutical Composition

The invention provides a pharmaceutical composition comprising anantibody of the invention. The composition may comprise a combination(such as two, three or four) of the antibodies of the invention. Thepharmaceutical composition may also comprise a pharmaceuticallyacceptable carrier.

The composition of the invention may include one or morepharmaceutically acceptable salts. A “pharmaceutically acceptable salt”refers to a salt that retains the desired biological activity of theparent compound and does not impart any undesired toxicological effects.Examples of such salts include acid addition salts and base additionsalts.

Suitable pharmaceutically acceptable carriers comprise aqueous carriersor diluents. Examples of suitable aqueous carriers include water,buffered water and saline.

Other suitable pharmaceutically acceptable carriers include ethanol,polyols (such as glycerol, propylene glycol, polyethylene glycol, andthe like), and suitable mixtures thereof, vegetable oils, such as oliveoil, and injectable organic esters, such as ethyl oleate. In many cases,it will be desirable to include isotonic agents, for example, sugars,polyalcohols such as mannitol, sorbitol, or sodium chloride in thecomposition.

Therapeutic compositions typically must be sterile and stable under theconditions of manufacture and storage. The composition can be formulatedas a solution, microemulsion, liposome, or other ordered structuresuitable to high drug concentration.

Pharmaceutical compositions of the invention may comprise additionaltherapeutic agents, for example an anti-viral agent. The anti-viralagent may bind to coronavirus and inhibit viral activity. Alternatively,the anti-viral agent may not bind directly to coronavirus but stillaffect viral activity/infectivity. The anti-viral agent could be afurther anti-coronavirus antibody, which binds somewhere on SARS-CoV-2other than the spike protein. Examples of an anti-viral agent usefulwith the invention include Remdesivir, Lopinavir, ritonavir, APN01, andFavilavir.

The additional therapeutic agent may be an anti-inflammatory agent, suchas a corticosteroid (e.g. Dexamethasone) or a non-steroidalanti-inflammatory drug (e.g. Tocilizumab).

The additional therapeutic agent may be an anti-coronavirus vaccine. Thepharmaceutical composition may be administered subcutaneously,intravenously, intradermally, intramuscularly, intranasally or orally.Also within the scope of the invention are kits comprising antibodies orother compositions of the invention and instructions for use. The kitmay further contain one or more additional reagents, such as anadditional therapeutic or prophylactic agent as discussed herein.

Methods and Uses of the Invention

The invention further relates to the use of the antibodies, thecombinations of the antibodies and the pharmaceutical compositions,described herein, e.g. in a method for treatment of the human or animalbody by therapy, or in a diagnostic method. The method of treatment maybe therapeutic or prophylactic.

For example, the invention relates to methods of treating coronavirus(e.g. SARS-CoV-2) infections, a disease or complication associatedtherewith, e.g. COVID-19. The method may comprise administering atherapeutically effective amount of an antibody, a combination ofantibodies, or a pharmaceutical composition of the invention. The methodmay further comprise identifying the presence of coronavirus, orfragments thereof, in a sample, e.g. SARS-CoV-2, from the subject. Theinvention also relates to an antibody, a combination of antibodies, or apharmaceutical composition according to the invention for use in amethod of treating coronavirus (e.g. SARS-CoV-2) infections, a diseaseor complication associated therewith, e.g. COVID-19.

The invention also relates to a method of formulating a composition fortreating coronavirus (e.g. SARS-CoV-2) infections, a disease orcomplication associated therewith, e.g. COVID-19, wherein said methodcomprises mixing an antibody, a combination of antibodies, or apharmaceutical composition according to the invention with an acceptablecarrier to prepare said composition.

The invention also relates to the use of an antibody, a combination ofantibodies, or a pharmaceutical composition according to the inventionfor treating coronavirus (e.g. SARS-CoV-2) infections or a disease orcomplication associated therewith, e.g. COVID-19.

The invention also relates to the use of an antibody, a combination ofantibodies, or a pharmaceutical composition according to the inventionfor the manufacture of a medicament for treating or preventingcoronavirus (e.g. SARS-CoV-2) infections or a disease or complicationassociated therewith, e.g. COVID-19.

The invention also relates to preventing, treating or diagnosingcoronavirus infection caused by any SARS-CoV-2 strain. The coronavirusinfection may be caused by any SARS-CoV-2 strain.

The SARS-CoV-2 strain may be the earliest identified Wuhan strain(hCoV-19/Wuhan/WIV04/2019 (WIV04); GISAID accession no. EPI_ISL_402124),and variants thereof. For example, the SARS-CoV-2 strain may be a memberof lineage A, A.1, A.2, A.3, A.5, B, B.1, B.1.1, B.2, B.3, B.4, B.1.1.7(alpha), B.1.351 (beta), P.1 (gamma), delta, kappa, and/or lambda. TheSARS-CoV-2 strain may be a member of lineage A.23.1, B.1.1.7 (alpha),B.1.351 (beta), B.1.258, B.1.526.2, B.1.616, B.1.617.1 (kappa),B.1.617.2 (delta), C36.3, C.37 (lambda), P.1 (gamma), B.1.1.529(omicron), Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and/or OmicronBA.3.

The SARS-CoV-2 strain may comprise one or more mutations, e.g. in thespike protein, relative to the hCoV-19/Wuhan/WIV04/2019 (WIV04) (GISAIDaccession no. EPI_ISL_402124). In other words, the SARS-CoV-2 strain maybe a modified hCoV-19/Wuhan/WIV04/2019 (WIV04) strain comprising one ormore modifications, e.g. in the spike protein.

The mutation may be the mutations (e.g. substitutions) observed in theOmicron strain of SARS-CoV-2.

Antibodies Omi02, Omi03, Omi12, Omi18, Omi28, Omi39 and Omi42 areparticularly effective in neutralising the Omicron SARS-Cov-2 strain.Hence, the invention may relate to these antibodies for use in treating,prevent, treating or diagnosing coronavirus infection caused by aSARS-Cov-2 strain.

The methods and uses of the invention may comprise inhibiting thedisease state (such as COVID-19), e.g. arresting its development; and/orrelieving the disease state (such as COVID-19), e.g. causing regressionof the disease state until a desired endpoint is reached.

The methods and uses of the invention may comprise the amelioration orthe reduction of the severity, duration or frequency of a symptom of thedisease state (such as COVID-19) (e.g. lessen the pain or discomfort),and such amelioration may or may not be directly affecting the disease.The symptoms or complications may be fever, headache, fatigue, loss ofappetite, myalgia, diarrhoea, vomiting, abdominal pain, dehydration,respiratory tract infections, cytokine storm, acute respiratory distresssyndrome (ARDS) sepsis, and/or organ failure (e.g. heart, kidneys,liver, GI, lungs).

The methods and uses of the invention may lead to a decrease in theviral load of coronavirus (e.g. SARS-CoV-2), e.g. by ≥10%, ≥20%, ≥30%,≥40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, or 100% compared to pre-treatment.Methods of determining viral load are well known in the art, e.g.infection assays.

The methods and uses of the invention may comprise preventing thecoronavirus infection from occurring in a subject (e.g. humans), inparticular, when such subject is predisposed to complications associatedwith coronavirus infection.

The invention also relates to identifying subjects that have acoronavirus infection, such as by SARS-CoV-2. For example, the methodsand uses of the invention may involve identifying the presence ofcoronavirus (e.g. SARS-CoV-2), or a protein or a fragment thereof, in asample. The detection may be carried out in vitro or in vivo. In certainembodiments, the invention relates to population screening.

The invention relates to identifying any SARS-CoV-2 strain, as describedherein. The invention may also relate to a method of identifying escapemutants of SARS-CoV-2, comprising contacting a sample with a combinationof antibodies of the invention and identifying if each antibody binds tothe virus. The term “escape mutants” refers to variants of SARS-CoV-2comprising non-silent mutations that may affect the efficacy of existingtreatments of SARS-CoV-2 infection. Typically, the non-silent mutationsis on an epitope recognised by a prior art antibody and/or antibodiesdescribed herein that specifically binds to an epitope of SARS-CoV-2,e.g. on the spike protein of SARS-CoV-2. If the antibody does not bindto the target, it may indicate that the target comprises a mutation thatmay alter the efficacy of existing SARS-CoV-2 treatments.

The methods and uses of the invention may include contacting a samplewith an antibody or a combination of the antibodies of the invention,and detecting the presence or absence of an antibody-antigen complex,wherein the presence of the antibody-antigen complex indicates that thesubject is infected with SARS-CoV-2.

Methods of determining the presence of an antibody-antigen complex areknown in the art. For example, in vitro detection techniques includeenzyme linked immunosorbent assays (ELISAs), Western blots,immunoprecipitations, and immunofluorescence. In vivo techniques includeintroducing into a subject a labelled anti-analyte protein antibody. Forexample, the antibody can be labelled with a radioactive marker whosepresence and location in a subject can be detected by standard imagingtechniques. The detection techniques may provide a qualitative or aquantitative readout depending on the assay employed.

Typically, the invention relates to methods and uses for a human subjectin need thereof. However, non-human animals such as rats, rabbits,sheep, pigs, cows, cats, or dogs is also contemplated. The subject maybe at risk of exposure to coronavirus infection, such as a healthcareworker or a person who has come into contact with an infectedindividual. A subject may have visited or be planning to visit a countryknown or suspected of having a coronavirus outbreak. A subject may alsobe at greater risk, such as an immunocompromised individual, for examplean individual receiving immunosuppressive therapy or an individualsuffering from human immunodeficiency syndrome (HIV) or acquired immunedeficiency syndrome (AIDS). The subject may be asymptomatic orpre-symptomatic.

The subject may be early, middle or late phase of the disease.

The subject may be in hospital or in the community at firstpresentation, and/or later times in hospital.

The subject may be male or female.

In certain embodiments, the subject is typically male. The subject maynot have been infected with coronavirus, such as SARS-CoV-2. The subjectmay have a predisposition to the more severe symptoms or complicationsassociated with coronavirus infections. The method or use of theinvention may comprise a step of identifying whether or not a patient isat risk of developing the more severe symptoms or complicationsassociated with coronavirus.

In embodiments of the invention relating to prevention or treatment, thesubject may or may not have been diagnosed to be infected withcoronavirus, such as SARS-CoV-2.

The invention relates to analysing samples from subjects. The sample maybe tissues, cells and biological fluids isolated from a subject, as wellas tissues, cells and fluids present within a subject. The sample may beblood and a fraction or component of blood including blood serum, bloodplasma, or lymph. Typically, the sample is from a throat swab, nasalswab, or saliva.

The antibody-antigen complex detection assays may be performed in situ,in which case the sample is a tissue section (fixed and/or frozen) ofthe tissue obtained from biopsies or resections from a subject.

In the embodiments of the invention where the antibodies pharmaceuticalcompositions and combinations are administered, they may be administeredsubcutaneously, intravenously, intradermally, orally, intranasally,intramuscularly or intracranially. Typically, the antibodiespharmaceutical compositions and combinations are administeredintravenously or subcutaneously.

The dose of an antibody may vary depending on the age and size of asubject, as well as on the disease, conditions and route ofadministration. Antibodies may be administered at a dose of about 0.1mg/kg body weight to a dose of about 100 mg/kg body weight, such as at adose of about 5 mg/kg to about 10 mg/kg. Antibodies may also beadministered at a dose of about 50 mg/kg, 10 mg/kg or about 5 mg/kg bodyweight.

A combination of the invention may for example be administered at a doseof about 5 mg/kg to about 10 mg/kg for each antibody, or at a dose ofabout 10 mg/kg or about 5 mg/kg for each antibody. Alternatively, acombination may be administered at a dose of about 5 mg/kg total (e.g. adose of 1.67 mg/kg of each antibody in a three antibody combination).

The antibody or combination of antibodies of the invention may beadministered in a multiple dosage regimen. For example, the initial dosemay be followed by administration of a second or plurality of subsequentdoses. The second and subsequent doses may be separated by anappropriate time.

As discussed above, the antibodies of the invention are typically usedin a single pharmaceutical composition/combination (co-formulated).However, the invention also generally includes the combined use ofantibodies of the invention in separate preparations/compositions. Theinvention also includes combined use of the antibodies with additionaltherapeutic agents, as described above.

Combined administration of the two or more agents and/or antibodies maybe achieved in a number of different ways. In one embodiment, all thecomponents may be administered together in a single composition. Inanother embodiment, each component may be administered separately aspart of a combined therapy.

For example, the antibody of the invention may be administered before,after or concurrently with another antibody, or binding fragmentthereof, of the invention. The particularly useful combinations aredescribed above for example.

For example, the antibody of the invention may be administered before,after or concurrently with an anti-viral agent or an anti-inflammatoryagent.

In embodiments where the invention relates to detecting the presence ofcoronavirus, e.g. SARS-CoV-2, or a protein or a fragment thereof, in asample, the antibody contains a detectable label. Methods of attaching alabel to an antibody are known in the art, e.g. by direct labelling ofthe antibody by coupling (i.e., physically linking) a detectablesubstance to the antibody. Alternatively, the antibody may be indirectlabelled, e.g. by reactivity with another reagent that is directlylabelled. Examples of indirect labelling include detection of a primaryantibody using a fluorescently-labelled secondary antibody andend-labelling of a DNA probe with biotin such that it can be detectedwith fluorescently-labelled streptavidin.

The detection may further comprise: (i) an agent known to be useful fordetecting the presence of coronavirus, e.g. SARS-CoV-2, or a protein ora fragment thereof, e.g. an antibody against other epitopes of the spikeprotein, or other proteins of the coronavirus, such as ananti-nucleocapsid antibody; and/or (ii) an agent known to not be capableof detecting the presence of coronavirus, e.g. SARS-CoV-2, or a fragmentthereof, i.e. providing a negative control.

In certain embodiments, the antibody is modified to have increasedstability.

Suitable modifications are explained above.

The invention also encompasses kits for detecting the presence ofcoronavirus, e.g. SARS-CoV-2, in a sample. For example, the kit maycomprise: a labelled antibody or a combination of labelled antibodies ofthe invention; means for determining the amount of coronavirus, e.g.SARS-CoV-2, in a sample; and means for comparing the amount ofcoronavirus, e.g. SARS-CoV-2, in the sample with a standard. Thelabelled antibody or the combination of labelled antibodies can bepackaged in a suitable container. The kit can further compriseinstructions for using the kit to detect coronavirus, e.g. SARS-CoV-2,in a sample. The kit may further comprise other agents known to beuseful for detecting the presence of coronavirus, as discussed above.

For example, the antibodies or combinations of antibodies of theinvention are used in a lateral flow test. Typically, the lateral flowtest kit is a hand-held device with an absorbent pad, which based on aseries of capillary beds, such as pieces of porous paper,microstructured polymer, or sintered polymer. The test runs the liquidsample along the surface of the pad with reactive molecules that show avisual positive or negative result. The test may further comprise usingother agents known to be useful for detecting the presence ofcoronavirus, e.g. SARS-CoV-2, or a fragment thereof, as discussed above,such as anti- an anti-nucleocapsid antibody.

Other

It is to be understood that different applications of the disclosedantibodies combinations, or pharmaceutical compositions of the inventionmay be tailored to the specific needs in the art. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments of the invention only, and is notintended to be limiting. In addition as used in this specification andthe appended claims, the singular forms “a”, “an”, and “the” includeplural references unless the content clearly dictates otherwise. Thus,for example, reference to “an antibody” includes two or more“antibodies”.

Furthermore, when referring to “≥x” herein, this means equal to orgreater than x. When referred to “≤x” herein, this means less than orequal to x.

For the purpose of this invention, in order to determine the percentidentity of two sequences (such as two polynucleotide or two polypeptidesequences), the sequences are aligned for optimal comparison purposes(e.g. gaps can be introduced in a first sequence for optimal alignmentwith a second sequence). The nucleotide or amino acid residues at eachposition are then compared. When a position in the first sequence isoccupied by the same nucleotide or amino acid as the correspondingposition in the second sequence, then the nucleotides or amino acids areidentical at that position. The percent identity between the twosequences is a function of the number of identical positions shared bythe sequences (i.e., % identity=number of identical positions/totalnumber of positions in the reference sequence×100). Typically thesequence comparison is carried out over the length of the referencesequence. For example, if the user wished to determine whether a given(“test”) sequence is 95% identical to SEQ ID NO: 3, SEQ ID NO: 3 wouldbe the reference sequence. To assess whether a sequence is at least 95%identical to SEQ ID NO: 3 (an example of a reference sequence), theskilled person would carry out an alignment over the length of SEQ IDNO: 3, and identify how many positions in the test sequence wereidentical to those of SEQ ID NO: 3. If at least 95% of the positions areidentical, the test sequence is at least 95% identical to SEQ ID NO: 3.If the sequence is shorter than SEQ ID NO: 3, the gaps or missingpositions should be considered to be non-identical positions. Theskilled person is aware of different computer programs that areavailable to determine the homology or identity between two sequences.For instance, a comparison of sequences and determination of percentidentity between two sequences can be accomplished using a mathematicalalgorithm. In an embodiment, the percent identity between two amino acidor nucleic acid sequences is determined using the Needleman and Wunsch(1970) algorithm which has been incorporated into the GAP program in theAccelrys GCG software package (available athttp://www.accelrys.com/products/gcg/), using either a Blosum 62 matrixor a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and alength weight of 1, 2, 3, 4, 5, or 6.

The CDRs of the heavy chain (CDRH) and light chain variable domain(CDRL) are located at residues 27-38 (CDR1), residues 56-65 (CDR2) andresidues 105-117 (CDR3) of each chain according to the IMGT numberingsystem (http://www.imgt.org; Lefranc MP, 1997, J, Immunol. Today, 18,509). This numbering system is used in the present specification exceptwhere otherwise indicated.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

The following examples illustrate the invention.

EXAMPLES Example 1. Generation of Antibodies Specific Against EarlyPandemic Sars-Cov-2 and Beta SARS-CoV-2 Strains

The antibodies in Table 1 relate to a set of mAbs generated againstearly pandemic strain of SARS-CoV-2. The antibodies in Table 2 relate toa set of mAbs generated against the Beta strain of SARS-CoV-2.

Further details of these antibodies may be found in internationalapplication no. PCT/GB2022/050306 & PCT/GB2022/050307. Furtherinformation on the generation and properties of these antibodies may befound in the following articles: Dejnirattisai, Wanwisa, et al. “Theantigenic anatomy of SARS-CoV-2 receptor binding domain.” Cell 184.8(2021): 2183-2200.

-   Supasa, Piyada, et al. “Reduced neutralization of SARS-CoV-2 B. 1.1.    7 variant by convalescent and vaccine sera.” Cell 184.8 (2021):    2201-2211.-   Liu, Chang, et al. “The antibody response to SARS-CoV-2 Beta    underscores the antigenic distance to other variants.” Cell host &    microbe (2021).-   Zhou, Daming, et al. “Evidence of escape of SARS-CoV-2 variant B.    1.351 from natural and vaccine-induced sera.” Cell 184.9 (2021):    2348-2361.-   Dejnirattisai, Wanwisa, et al. “Antibody evasion by the P. 1 strain    of SARS-CoV-2.” Cell 184.11 (2021): 2939-2954.-   Liu, Chang, et al. “Reduced neutralization of SARS-CoV-2 B. 1.617 by    vaccine and convalescent serum.” Cell 184.16 (2021): 4220-4236.-   Dejnirattisai, Wanwisa, et al. “SARS-CoV-2 Omicron-B. 1.1. 529 leads    to widespread escape from neutralizing antibody responses.” Cell    (2022).

Example 2. Generation of Antibodies Specific Against the Omicron Strainsof SARS-CoV-2 Omicron BA.2 Lineage

Omicron BA.2 was first reported from South Africa on the 17 Nov. 2021,at a similar time that Omicron BA.1 was reported. BA.2 has beenincreasing relative to BA.1 in a number of countries such as Denmark,India and the UK and now accounts for the majority of Omicron infectionsin Denmark and evidence is accruing that BA.2 is more transmissible thanBA.1, but there is no evidence for increased disease severity.

BA.2 is related to BA.1 sharing 21 amino acid substitutions spreadthroughout in S, however there are a number of differences BA.1, has anadditional 6 amino acid deletions, 3 insertions and 9 substitutionscompared to BA.2 and BA.2 has an additional 3 deletions and 7substitutions compared to BA.1. In the RBD, BA.1 contains uniquemutations S371L, G446S and G496S and in some isolates R346K (BA.1.1),while BA.2 carries S371F, T376A, D405N and R408S. All of these residueshave the potential to differentially affect antibody binding and couldmodulate neutralization, particularly BA.1 G446S, G496S, BA.2 D405N,R408S which lie at the edge of the ACE2 binding footprint and for BA.1.1the R346K change lies close to the N343 glycan and could modulatebinding of potent antibodies to this region. BA.3 contains no uniquemutations relative to BA.1 and BA.2 and appears to be a fusion of thetwo, being BA.1 like at the N terminus and switching to become BA.2 likeat the C-terminus from the mutation G496S.

Omicron Lineages BA.4 and BA.5

In early April 2022 two new Omicron lineages were reported from Gautengin South Africa and designated BA.4 and BA.5. The BA.4 and BA.5 Ssequences are identical, and closely related to BA.2. Sequence diversityin Omicron S is shown in FIG. 9 . Compared to BA.2, BA.4 has residues 69and 70 deleted, and contains 2 additional substitutions in the RBD:L452R and F486V. Finally BA.4 lacks the Q493R change seen in BA.1 andBA.2, reverting to Q493 as in the Victoria/Wuhan strain.

The 2 additional mutations in the RBD are of most concern in terms ofantibody escape: L452R is a chemically radical change and is one of thepair of changes in Delta RBD (the other, T478K, is already found in theOmicron lineage). Mutation F486L was found in sequences of SARS-CoV-2isolated from Mink early in the pandemic and is also a site of escapemutations to several mAbs (Gobeil et al., 2021, “Effect of naturalmutations of SARS-CoV-2 on spike structure, conformation, andantigenicity”. Science 373, 6555). The change F486V in BA.4/5 is also areduction in the bulk of the hydrophobic side-chain as in F486L, butmore significant. Both residues 452 and 486 lie close to the edge of theACE2 interaction surface (FIG. 9B) and both, together with the reversionto ancestral sequence Q493 which lies within the ACE2 footprint, havethe potential to modulate ACE2 affinity as well as modulate theneutralizing capacity of vaccine or naturally acquired serum. The L452Rand F486V mutations are likely to cause more antibody escape, while thereversion at 493 may reduce the escape from responses to earlierviruses.

The Omicron Lineage BA.2.75

In early May 2022, a new Omicron BA.2 sublineage designated BA.2.75 wasreported in India. It has spread to multiple countries, including theUK, US, Australia, Germany and Canada. BA.2.75 contains multiplemutational changes in the S protein compared to BA.2, including foursubstitutions in the NTD (W152R, F157L, I210V and G257S) and four in theRBD: D339H, G446S, N460K and R493Q (FIG. 16 ). The RBD mutations impingeon major epitopes for neutralising antibodies and are likely to modulateACE2 binding. D339H represents a further evolution of the G339D mutationfound in all previous Omicron variants that has been found to impair thebinding of certain ‘right-flank’ antibodies belonging to the IGHV1-69family (e.g. Beta-49 and -50); it also falls in the binding footprint ofcertain Class 3 antibodies such as S309/sotrovimab (Dejnirattisai etal., 2022; “SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape fromneutralizing antibody responses.” Cell 185, 467-484 e415). G446S wasfound in BA.1, BA.1.1 and BA.3 but not in BA.2 and other BA.2subvariants, and is also able to impair binding of certain Class 3antibodies binding the right shoulder such as REGN10987/imdevimab(Dejnirattisai et al., 2022). The R493Q reversion was also found inBA.4/5, and may make the virus more sensitive to neutralization by anumber of class 1 and 2 antibodies binding the neck/left shoulder. Thisreversion may also increase the affinity for ACE2 (see below).

N460K is a novel mutation not seen in previous VoC or Omicronsublineages, but it was found after in vitro (yeast display) evolutionin RBD-62 which has an ultra-high ACE2 affinity (KD=16-18 pM)(Dejnirattisai et al., 2022; Zahradnik et al., 2021 “SARS-CoV-2 variantprediction and antiviral drug design are enabled by RBD in vitroevolution”. Nat Microbiol 6, 1188-1198). Indeed N460K led to substantialincrease in affinity for ACE2, second only to the effect of N501Y(Zahradnik et al., 2021). Furthermore, in silico analysis predicts thatN460K may affect the binding of certain antibodies belonging to theIGHV3-53 family (e.g. Omi-3) which have been shown to be able topotently neutralise all VoC (Nutalai et al., 2022).

Using neutralization assays, Delta infection in isolation was show toprovide no protection (no neutralization) against BA.2.75. The mutationsin BA.2.75 lead to a reduction in neutralization titres of vaccine serumcompared to BA.2. Individual BA.2.75 mutations can cause greaterreduction in neutralization titres compared to the full BA.2.75 Ssequence, but these are balanced by the R393Q reversion mutation, whichmay have been selected to increase affinity to ACE2 and increase thetransmissibility of BA.2.75. It seems inevitable that further evolutionof the Omicron lineage will occur and there are likely many possibletrade-offs between antibody escape and ACE2 affinity, that can and willbe made, leading to successive waves of infection.

Emerging BA.2, BA.4 and BA.5 Sublineages

A number of lineages are growing rapidly from within both the BA.2 andBA.5 branches. Most striking, is the large degree of convergentevolution, particularly at antigenic RBD positions such as 346, 444,452, 460, 486, 490, 493 and 494. These lineages include examples fromthe BA.4/5 branches (which contain L452R, F486V and the reversionR493Q), such as BA.4.6 and BF.7 (R346T), BA.4.7 (R346S), BQ.1 (K444T,N460K) and BQ.1.1 (R346T, K444T, N460K); from the BA.2.75 branch (whichcontains G339H, G446S, N460K and the reversion R493Q), BA.2.75.2 (R346Tand F486S and BA.2.75 mutations), BN.1 (aka BA.2.75.5.1 with R346T,K356T, F490S and BA.2.75 mutations), BM.1.1.1 (aka BA.2.75.3.1.1.1 withR346T, F486S, F490S and BA.2.75 mutations). There are also examples ofseveral other second generation BA.2 variant lines such as BJ.1 (akaBA.2.10.1.1; G339H, R346T, L368I, V445P, G446S, V483A and F490V),BA.2.10.4 (G446S, F486P, S494P and the R493Q reversion), BS.1 (akaBA.2.3.2.1; R346T, L452R, N460K, G476S and the Q493R reversion),BA.2.3.20 (K444R, N450D, L452M, N460K, E484R and the Q493R reversion),and finally a BJ.1×BM.1.1.1 (aka BA.2.75.3.1.1.1) recombinant, XBB(which relative to BA.2 contains R346T, L368I, V445P, G446S, N460K,F486S, F490S and the Q493R reversion).

Outside the RBD the degree of convergent evolution is lesser but stillpresent. Many of the second-generation BA.2 variant lineages containdeletions or mutations in the NTD, often similar to those seen in theVoCs, for example A-144 in BJ.1, BS.1, and BA.2.10.4 (previously seen inAlpha and BA.1) and NSP12 G671S in BJ.1, XBB and BA.2.10.4 (previouslyseen in Delta).

Potently Neutralizing Antibodies Isolated Following Omicron Infection

Five volunteers who had recovered from sequence confirmed Omicroninfection were recruited and sampled them 10-14 days following symptomonset; all volunteers had received 2 doses of the Pfizer BioNtechvaccine before being infected with Omicron. First, neutralization assayswere performed against Omicron BA.1 and Victoria (an early pandemicSARS-CoV-2 isolate containing only a single amino acid substitution in SNTD (S247R) compared to the sequence of the Wuhan stain used in allcurrent vaccines). In all cases the focus reduction neutralization 50%titre (FRNT50) to Omicron was above 100, but at this early time pointthe titres were considerably below the titres to Victoria (FIG. 1A).

B cells from the five donors were stained with full length BA.1 trimerand single cells sorted by FACS (FIG. 1B). Following a degenerate RT-PCRreaction, heavy and light chain sequences were assembled into expressionvectors using the Gibson reaction and the products transfected into 293Tcells. Culture supernatants were screened for reactivity to full lengthBA.1 or wild type S (WT Wuhan) together with BA.1 RBD and NTD. In total1,122 single cells were sorted and 545 mAb recovered.

All mAbs cross-reacted between WT and BA.1 S by ELISA, suggesting thatthey could have been generated from memory B cells induced byvaccination. In contrast to a previous panel of monoclonal antibodieswere produced from naïve cases infected early during the pandemic(Dejnirattisai, Wanwisa, et al. “The antigenic anatomy of SARS-CoV-2receptor binding domain.” Cell 184.8 (2021): 2183-2200), a higherproportion the omicron-specific mAbs were found to react to the RBD(56%) when compared to the early pandemic mAbs (21%, p<0.0001) (FIG.1C). In addition 129 of the 545 isolated mAbs bound the BA.1 NTD.

Isolation of Potent Omicron mAb

Neutralization assays were performed on all ELISA positive mAb and thoseshowing the highest activity were chosen for further study. The mostpotent 28 mAbs were selected for full characterization all of whichshowed BA.1 FRNT50 titres<100 ng/ml. 27/28 bound the RBD (one, Omi-41bound the NTD) and none cross-reacted with SARS-CoV-1 S protein byELISA.

Examination of gene usage (FIG. 1D, Table 17) revealed that 9/28 mAbsbelong to the VH3-53 and the related VH3-66 gene families. VH3-53 andVH3-66 have been isolated repeatedly in SARS-CoV-2 infection, they forma public antibody response and bind to a site on the neck of the RBD andfunction to block ACE2 binding. It was previously observed that manyVH3-53 and VH3-66 mAbs lose activity on VoCs containing the N501Ymutation, although some VH3-53 antibodies (mAb 222 and Beta-27) werefully resistant to the N501Y change found in Alpha, Beta and Gamma butsuffered knock down of activity to Omicron BA.1 or BA.2.

Roughly one half of the gene families observed in the potent earlypandemic antibodies (Table 1) are also represented in the Omicron set(FIG. 1C), perhaps the most notable difference is that VH1-69 does notfeature in the early antibodies but is found in 6/28 of the potentOmicron set (2, 24, 30, 31, 34 and 38) and we also found it in 2 Betaantibodies, Beta 49 and 50, which bind to a site in proximity to theN343 glycan. Analysis of the Omicron mAb shows much longer CDR3sequences suggesting a different mode of binding than Beta 49, 50. Inthe Beta set of mAb, expansion of a public response was found to bemediated through VH 4-39 (6/27 mAb), which bound an epitope around the501Y mutation, most lost activity against BA.1 and it is noteworthy thatnone of the current set of Omicron mAb are encoded by VH4-39.

Compared to the early pandemic set of antibodies we found higher levelsof somatic mutation in both heavy and light chains compared to the earlypandemic set of mAb Omicron (mean of 9.00, 6.00 and early pandemic 4.55,4.25 for VH and VL respectively). These results would be consistent withthe evolution of increased Omicron affinity via somatic mutation ofvaccine induced memory B cells.

Broad Neutralization of VoC by Omicron mAb

Neutralization assays were performed against Victoria and all variantsof concern Alpha, Beta, Gamma, Delta and Omicron BA.1, for the panel of28 potent mAbs (FIGS. 2A-C, Tables 13 to 16 and 18). The likely originof all of these antibodies from vaccine induced memory B cells isapparent in that in almost all cases, FRNT50 titres to Victoria are atthe high end of all VoC tested for each mAb (FIGS. 2A-C, Tables 13 to 16and 18). Five of the mAbs neutralize BA.1 with FRNT50 titres<10 ng/ml,mAb Omi-3, 8, 12, 18 and 24 are the most potent with FRNT50 titres of 9,8, 4, 6, 7 ng/ml and FRNT90 titres of 67, 42, 20, 18, 35 ng/mlrespectively.

The data provided in Tables 13, 14 and 16 include some IC₅₀ dataobtained using pseudoviral constructs. The data in Table 18 consists ofIC₅₀ results obtained exclusively from authentic virus constructs.

17/28 antibodies are cross-reactive against all VoC with <10-folddifference in FRNT50 titres between all viruses. Omi-06, 24, 30, 31, 34and 41 show reduced or absent activity against Delta, with 3/6 of thesebelonging to the VH1-69 family, and may have an epitope impinging on theL452R Delta mutation (Delta shares T478K with BA.1). Antibodies Omi-09and 32 perform poorly on Beta and Gamma and may be sensitive to E484Kfound in Beta and Gamma, but may tolerate the E484A change in Omicron(Omicron shares N501Y and K417N with Beta whilst Gamma is N501Y, K417T).Finally, although 129 anti-NTD mAbs were isolated only one of these,Omi-41, showed FRNT50 titres<100 ng/ml, Omi-41 showed neutralizingactivity against Victoria, Alpha, Beta and Gamma but no activity againstDelta, presumably resulting from the unique spectrum of NTD changesfound in Delta.

Neutralization of BA.1 Compared to BA.1.1, BA.2 and BA.3

Lentiviral based reporters were constructed pseudotyped with the S genesequences for Victoria, BA.1, BA.1.1, BA.2 and BA.3. Neutralizationassays against the Omicron mAb are shown in FIG. 2B, Tables 14 and 18,most antibodies show little difference in neutralization of BA.1,BA.1.1, BA.2 and BA.3. However, there were some notable exceptions; BA.2neutralization was reduced 38, 3 and 158-fold compared to BA.1 forOmi-8, 29 and 32 respectively, while BA.1.1 neutralization was reduced40.9, 10.8, 7.8 and 6.6-fold compared to BA.1 for Omi-6, 24, 34 and 35respectively and knocked out for Omi-39 and 40. BA.3 neutralization bythe Omi-mAb mirrored that found with BA.2 with the exception of Omi-06and Omi-36 where BA.3 neutralization titres were considerably lower thaneither BA.1 or BA.2. For some reason the NTD binding mAb Omi-41 did notneutralize Victoria in the pseudoviral system but did neutralize livevirus, this was also found with early pandemic mAb 159 which showedpotent activity on live virus but no activity on pseudovirus.

Pseudoviral neutralization curves for panels of mAb isolated from earlypandemic cases together with mAb isolated from Beta cases is shown inFIGS. 4A, B, Table 15, in most cases, neutralization titres againstBA.1, BA.1.1 and BA.2 are similar, but there are some differences, mAbs40, 278 and 318 neutralize BA.2>BA.1, whereas 222, Beta 22, 29, 54, 55and 56 neutralize BA.1 better than BA.2, whilst Beta-53 which bindsclose to the N343 glycan shows reduced neutralization of BA.1.1.

Neutralization by Antibodies Developed for Clinical Use.

Finally, neutralization of Victoria, BA.1, BA.1.1, BA.2 and BA.3 strainswas tested using mAbs being developed for clinical use where a number ofdifferences were found (FIG. 2C, Tables 16 and 18). Interestingly,activity of Known Antibody A (REGN 10987) was partially restored on BA.2but still 308-fold reduced compared to Victoria, Activity of Knownantibody C (AZD1061) was almost completely restored on BA.2, whilstKnown antibody D (AZD8895) was 5.4-fold reduced on BA.2 vs BA.1 and thecombination of both Known antibody D (AZD8895) and E, was only reduced8-fold compared to Victoria. The activity of Known Antibody K (S309) was6.8-fold reduced on BA.2 compared to BA.1, Finally the activity of KnownAntibody G (ADG20) was completely lost on BA.2.

In summary, the neutralization of most Omicron monoclonal antibodies arenot affected by the differences between BA.1, BA.1.1, BA.2 or BA.3mutations. Some monoclonal antibodies do however show differences, inparticular Known Antibody A (REGN 10987) and Known antibody C (AZD1061)which neutralize BA.2 more easily than BA.1 and Known Antibody K (S309)which shows reduced neutralization of BA.2 and this may encouragesub-lineage typing before use. The structural explanations for thedifferences between BA.1, BA.1.1, BA.2 and BA.3 neutralization will bediscussed below.

Neutralization of BA.1, BA.1.1, BA.2 and BA3 by Immune Sera

To determine whether the differences in transmissibility between BA.1and BA.2 may be due to differential neutralization and also to determinewhether there was a possibility that BA.2 could escape the BA.1 antibodyresponse, neutralization assays were performed using sera from a varietyof sources. First, neutralization assays were performed on Victoria,BA.1, BA.1.1, BA.2 and BA.3 using sera collected from vaccineesreceiving the Oxford/AstraZeneca AZD1222 (n=41) or Pfizer/BioNtechBNT162b2 (n=20) vaccines (FIGS. 3A, B).

For AZD 1222 samples were taken 4 weeks after the second and third dosesof vaccine. Following the third dose of AZD 1222 there were small butsignificant differences between pseudoviral neutralization withreductions of the titres against BA.2 vs BA.1 (1.17-fold p=0.0019) andBA.1.1 vs BA.1 (1.29-fold p=0.0086). For BNT162b2 samples were taken 4weeks and 6 months following the second dose of vaccine, before thethird dose and 4 weeks after the third dose. Following the third vaccinedose, titres against BA.1, BA.2 and BA.1.1 were similar with nonsignificant differences between them. Next, the neutralization profileof serum collected from cases infected with Omicron were determined.Early samples (n=12) were taken <14 days from symptom onset (median 13days), later samples (n=17) were taken >21 days following symptom onset(median 38 days). All cases had received at least 2 doses of vaccine anda number of the late convalescent cases received a third dose of vaccinefollowing Omicron infection. Neutralization against Victoria, Alpha,Beta, Gamma, Delta and Omicron was tested using live virusneutralization assays (FIG. 3C). At early time points, all vaccinatedcases had high titres to Victoria with geometric mean FRNT50 close to1/3000 and exhibited broad neutralization of VoC with FRNT50>1/1000 forall viruses except Omicron (FRNT50=558). At the later time point titresagainst Victoria were unchanged whilst there were increases in titres tothe VoC and Omicron (3-fold p=0.0123). Pairwise comparison of early andlate samples taken from the same individuals confirmed the broadboosting of the response following Omicron infection (FIG. 5A)

Neutralization of Victoria, BA.1, BA.1.1, BA.2 and BA.3 was assayed bypseudoviral neutralization. BA.1 neutralization titres were higher atlater time points. However, all of the sera were obtained from BA.1infected cases and there were small but significant reductions in theneutralization titres of BA.2 vs BA.1 (1.7 and 1.5-fold p=0.0034 and0.0067 at <14 and >21 days respectively), the titres of BA.1.1 vs BA.1were not significantly reduced while at >21 days the titre against BA.3vs BA.1 was reduced 1.7-fold (p=0.0012) (FIGS. 3D, 5B).

In summary, following three doses of vaccine, particularly BNT162b2,good neutralizing titres of antibody against Omicron BA.1 BA.1.1, BA.2and BA.3 are induced, with only minor differences between the titreagainst BA.1 BA.1.1, BA.2 and BA.3. This may indicate that the increasedtransmissibility of BA.2 is not due to increased vaccine escape.Following break through Omicron infection, in previously vaccinatedindividuals, there is boosting of a broad antibody response to variantsof concern and the generation of strong responses to Omicron. Sincethere are only small differences in the neutralization between BA.1 andBA.2, BA.2 superinfection of BA.1 exposed and vaccinated cases isunlikely, at least in the short term.

Neutralization of BA.4 Compared to BA.1, BA.1.1, BA.2 and BA.3

Neutralization of BA.4/5 was also assessed in comparison to Omicronsub-lineages BA.1, BA.1.1, BA.2, BA.3 and the early pandemic Victoriastrain. BA.4/5 was shown to have a more extreme antibody escapephenotype than BA.1 and BA.2, and serum from triple vaccinated donorshad ˜2-3-fold reduction in neutralization titres compared to theneutralization of BA.1 and BA.2. Additionally, serum from breakthroughBA.1 infections in vaccinees showed ˜2-3-fold reduction inneutralization titres to BA.4/5 compared to BA.1 and BA.2. This suggeststhat currently approved vaccines and mAbs may be less effective atpreventing BA.4/5 transmission. New monoclonals and combinations maytherefore be needed to plug the gap to protect the extremely vulnerableand those unable to mount adequate vaccine responses.

Neutralization of BA.4 by Vaccine Serum

A panel of pseudotyped lentiviruses (Di Genova et al., 2020,“Production, titration, neutralisation and storage of SARS-CoV-2lentiviral pseudotypes”. Figshare preprint.) expressing the S gene fromthe Omicron sub-lineages BA.1, BA.1.1, BA.2, BA.3 and BA.4/5 wasconstructed, together with early pandemic Wuhan related strain,Victoria, used as a control.

Neutralization assays were performed using serum obtained 28 daysfollowing a third dose of the Oxford-AstraZeneca vaccine ADZ 1222(n=41)) (Flaxman et al, 2021, “Reactogenicity and immunogenicity after alate second dose or a third dose of ChAdOx1 nCoV-19 in the UK: asubstudy of two randomised controlled trials (COV001 and COV002)”.Lancet 398, 981-990.) or the Pfizer-BioNtech vaccine BNT162b2) (Cele etal., 2021, “Omicron extensively but incompletely escapes Pfizer BNT162b2neutralization”. Nature 602, 654-666) (n=20) (FIGS. 7 A,B). For AZD1222neutralization titres for BA.4 were reduced 2.1-fold compared to BA.1(p=0.0001) and 1.8-fold compared to BA.2 (p=0.0001). For BNT162b2neutralization titres were reduced 3.2-fold (p=0.0001) and 3.1-fold(p=0.0001) compared to BA.1 and BA.2 respectively. These reductions intitre are likely to reduce vaccine effectiveness particularly at longertime points as antibody titres naturally wane.

Neutralization of BA.4/5 by Serum from Breakthrough BA.1 Infection

At the onset of the Omicron outbreak, vaccinated volunteers who hadsuffered breakthrough Omicron infections were recruited. Samples werefirst taken ≤14 days from symptom onset (median 13 days), while latesamples were taken ≥21 days from symptom onset (median 38 days) n=16.Pseudoviral neutralization assays were performed against the panel ofpseudoviruses representing variants of concern and the OmicronSub-lineages (FIGS. 7 C, D).

BA.1 infection following vaccination leads to a broad neutralizingresponse, with high titres to all the VoC, which is boosted at latertime points (Nutalai et al. 2022, “Potent cross-reactive antibodiesfollowing Omicron breakthrough in vaccines”. Cell (in press)).Neutralization titres against BA.4 were significantly less than BA.1 andBA.2, at the early time point BA.4/5 titres were reduced 1.9-fold(p=0.0001) and 1.5-fold (p=0.0015) compared to BA.1 and BA.2respectively. At the later point BA.4/5 titres were reduced 3.4-fold(p=0.0001) and 2-fold (p=0.0017) compared to BA.1 and BA.2 respectively.

Thus, BA.4/5 shows a degree of immune escape from the vaccine/BA.1response when compared with BA.1 and BA.2. These samples were all takenreasonably close to the time of infection meaning that further waning inthe intervening months may render individuals susceptible to reinfectionwith BA.4/5.

Escape from Monoclonal Antibodies by BA.4/5

Sensitivity to L452R: It has previously been reported that Omi-24, 30,31, 34 and 41 show complete knock out of neutralizing activity againstDelta, with Omi-06 showing severe knock-down of activity (Nutalai etal., 2022). Since BA.1 and BA.2 harbour only one (T478K) of the 2 DeltaRBD mutations, whilst BA.4/5 also harbour L452R, it is expected that allfive of these L452 directed mAbs to be knocked out on BA.4/5. This isindeed observed (FIG. 8A, Table 20). Omi-41 also fails to neutralize,which is attributed to the differences in mutations in the NTD (FIG.9A).

To confirm that the neutralization effects observed are directlyattributable to alterations in RBD interactions, binding analyses ofselected antibodies to BA.4/5 and BA.2 RBDs by surface plasmon resonance(SPR) were also performed (FIGS. 10, 15 ). Omi-31 was chosen asrepresentative of the set of L452R sensitive antibodies, and as expectedthe binding is severely affected (FIG. 10A).

Since detailed information on the interaction of several Omicronresponsive antibodies with the RBD is available, the BA.4/5 RBDmutations were modelled in the context of known structures for OmicronFabs complexed with BA.1 or Delta RBDs (Dejnirattisai et al., 2022,“SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape fromneutralizing antibody responses”. Cell 185, 467-484 e415; Nutalai etal., 2022), (FIG. 11 ). The Omi-31 complex is shown in FIG. 11A andshows L452 tucked neatly into a hydrophobic pocket, which is unable toaccommodate the larger positively charged arginine in BA.4/5 and Delta.

L452R enhancement of binding: Omi-32 shows 77-fold enhancedneutralization of BA.4/5 compared to BA.2. Kinetic analysis of Fabbinding to the RBDs suggests that this is mainly achieved by a 5-foldincrease in the on-rate of binding (FIGS. 10B, C). This is largelyexplained by the favorable interaction of the arginine at 452 making asalt bridge to residue 99 of the heavy chain (HC) CDR3 (FIG. 11B),perhaps assisted by removal of slightly unfavourable charge interactionsat residue 493. It is possible that these electrostatic changes enhanceon-rate by electrostatic steering of the incoming antibody.

Sensitivity to F486V: Extending the logic used to understand Deltasensitivity, the remaining antibodies affected by BA.4/5>BA.2, but whichretain activity against Delta, are likely sensitive to the F486V change,namely Omi-02, 09, 12, 23, 25, 26, 29. The binding sensitivity wasconfirmed by SPR analysis of Omi-12 (FIGS. 10D, E) which showed analmost 1,000-fold reduction in affinity. An example of the structuralbasis of sensitivity is provided by the Omi-25 complex (FIG. 11C), whichshows that the phenylalanine side chain acts as a binding hot-spot,nestled in a hydrophobic cavity making favorable ring-stackinginteractions with Y106 of the HC CDR3.

Activity of Commercial Antibodies Against BA.4 and BA.5

A panel of antibodies that have been developed fortherapeutic/prophylactic use was tested against BA.4/5 (FIG. 8B, Table21). Many of these antibodies have already suffered severe reductions orknock out of activity against BA.1, BA.1.1 or BA.2. For AstraZenecaAZD1061, activity to BA.4/5 was similar to BA.2 (<2-fold reduction),whilst for AZD8895 residual activity against BA.2 was knocked out. Theactivity of the combination of both antibodies in AZD7442 (Dong et al.,2021, “Genetic and structural basis for recognition of SARS-CoV-2 spikeprotein by a two-antibody cocktail”. Nature Microbiol. 6, 1233-1244) wasreduced 8.1-fold compared with BA.2. The residual activity of REG10987(Weinreich et al., 2021, “REGN-COV2, a Neutralizing Antibody Cocktail,in Outpatients with Covid-19”. N Engl J Med 384, 238-251) against BA.2was further reduced on BA.4/5, likewise residual BA.1 neutralizingactivity was knocked out for ADG20 (Yuan et al., 2022, “A broad andpotent neutralization epitope in SARS-related coronaviruses”. bioRxiv.https://doi.org/10.1101/2022.03.13.484037) on BA.4/5. For S309(VIR-7831/7832) (Sun and Ho, 2020, “Emerging antibody-based therapeuticsagainst SARS-CoV-2 during the global pandemic”. Antib Ther 3, 246-256.),activity against BA.4/5 was 1.6 fold reduced compared to BA.2.

These effects can be rationalized by reference to the way the antibodiesinteract with the RBD, for instance in the case of AZD8895 (an IGHV1-58genotype mAb, FIG. 11E), F486 forms a hydrophobic interaction hotspotwhich will be abrogated by the mutation to a much smaller valinesidechain. Antibody residues involved in the interactions with F486 arehighly conserved among this genotype of mAbs, including Omi-12, 253 andBeta-47 (Nutalai et al., 2022, “Potent cross-reactive antibodiesfollowing Omicron breakthrough in vaccines”. Cell (in press);Dejnirattisai et al., 2021, “The antigenic anatomy of SARS-CoV-2receptor binding domain”. Cell 184, 2183-2200 e2122; Liu et al., 2021,“The Beta mAb response underscores the antigenic distance to otherSARS-CoV-2 variants”. Cell, Host and Microbe 30, 53-68), explaining thesevere effect of the F486V mutation on neutralization of these mAbs(FIGS. 8A, 13 ).

Neutralisation of BA.2.75 by Vaccine Serum

A panel of pseudotyped lentiviruses was constructed as above (Di Genovaet al., 2020) expressing the S gene from the Omicron sub-lineages BA.1,BA.1.1, BA.2, BA.2.12.1, BA.4/5, BA.2.75, together with Victoria, anearly pandemic Wuhan related strain, used as a control. D339H, G446S,N460K and R493Q were also included as single mutations on the BA.2background. Neutralization assays were performed using serum obtained 28days following a third dose of the Oxford-AstraZeneca vaccine AZD1222(n=41) (Flaxman et al., 2021 “Reactogenicity and immunogenicity after alate second dose or a third dose of ChAdOx1 nCoV-19 in the UK: asubstudy of two randomised controlled trials (COV001 and COV002).”Lancet 398, 981-990) or of Pfizer-BioNtech vaccine BNT162b2 (n=22) (Celeet al., 2021; “Omicron extensively but incompletely escapes PfizerBNT162b2 neutralization”. Nature 602, 654-666e) (FIG. 17 ). For AZD1222,neutralization of BA.2.75 was reduced 1.2-fold compared to BA.2(p=0.0182) and 1.1-fold compared to BA.2.12.1 (p=0.0065), but increased1.5-fold compared to BA.4/5 (p<0.0001) (FIG. 17B). Overall, there arereductions in BA.2.75 neutralization titres of vaccine serum compared toBA.2 but not to the level seen with BA.4/5.

Neutralization of BA.2.75 by Serum from Vaccine Breakthrough BA.1 orBA.2 Infections

Breakthrough BA.1 serum samples were taken from vaccinated volunteers≥28 days from symptom onset (median 38 days; n=16). Pseudoviralneutralization assays were performed against the panel of pseudovirusesdescribed above (FIG. 17C). Neutralisation titres for BA.2.75 weresimilar to BA.2, and 1.4-fold (p=0.0052) and 2.0-fold (p=0.0001) higherthan BA.2.12.1 and BA.4/5 respectively, suggesting that BA.2.75 might beless likely to cause reinfections in individuals who have suffered BA.1breakthrough infections than BA.2.12.1 or BA.4/5.

Breakthrough BA.2 serum samples were taken from vaccinated volunteers≥12 days from symptom onset (median 29 days; n=23). Pseudoviralneutralization assays were performed against the panel of pseudovirusesVictoria, BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5 and BA.2.75 (FIG. 17D).Here, neutralization titres against BA.2.75 were significantly reducedcompared to BA.2 (1.4-fold; P=0.0021), similar to BA.2.12.1, but stillhigher than BA.4/5 (1.4-fold; P=0.0123). Taken together, BA.2.75 shows adegree of escape from humoral response induced by BA.2 breakthroughinfection but not BA.1 infection.

Individual BA.2.75 Mutation have Differential Effects on Neutralization

To understand the effects of the individual mutations in the BA.2.75RBD, these mutations were introduced individually into the pseudovirusBA.2 background and their neutralization was assayed using triplevaccinated Pfizer BNT162b2 serum (FIG. 17E). Neutralization titres forBA.2 were reduced for 3/4 single mutation variants of BA.2, with thegreatest decrease for N460K (3.1-fold, p<0.0001), followed by D339H(1.3-fold, p=0.0006), then by G446S (1.2-fold, p=0.2312), howeverneutralization titres were increased 1.5-fold by the R493Q reversionmutation (p<0.0001). Q493 is present in all vaccines thus explaining theincrease in activity of vaccine serum to this reversion mutation.

Escape from Monoclonal Antibodies by BA.2.75

To dissect how BA.2.75 might affect neutralising antibody activity,pseudoviral assays were used to test a recently reported panel of potenthuman mAbs generated from cases of Omicron breakthrough infection (BA.1IC50 titres<0.1 μg/ml) (Nutalai et al., 2022.) (FIG. 19A, Table 22).Among the 27 RBD-specific mAbs, those belonging to the IGHV3-53/66families are most severely affected. Three (Omi-16, Omi-29 and Omi-36)showed a complete knock out of BA.2.75 neutralization; an additionalfour (Omi-18, Omi-20, Omi-27 and Omi-28) showed >5-fold reductioncompared to BA.2, which is in line with the observation that N460interacts with highly conserved GGS/T motif of CDR-H2 in the structuresof RBD/IGHV-3/66 complexes (FIG. 21B) (Dejnirattisai et al. 2021, Liu etal. 2021, Nutalai et al. 2022).

Like BA.2 and BA.4/5, BA.2.75 is not neutralised by the anti-NTD mAbOmi-41, which only interacts with the NTD of BA.1, BA.1.1 and BA.3.

The Omi mAbs were also tested against the pseudoviruses encoding singlepoint mutations in the BA.2 RBD described above (FIG. 23 , Table 24).The VH3-53/66 mAbs that lost neutralization to BA.2.75 were alsoimpacted by the N460K mutation, confirming the prediction that thisresidue was critical for the binding of a number of members of thispublic gene family. Interestingly, The BA.2+N460K mutation in isolationshows a larger impact than BA.2.75 on the activity of several mAbs: theneutralisation titre of Omi-03 (IGHV3-53) was reduced 50-fold forBA.2+N460K but only 2-fold for BA.2.75; Omi-17 (IGHV3-66) was completelyknocked out on BA.2+N460K but only reduced 4-fold for BA.2.75; andOmi-33 (IGHV3-33) was reduced 7-fold for BA.2+N460K but there was nochange observed for BA.2.75. Thus, other mutations in BA.2.75 might havemitigated the effect of the N460K mutation, particularly the R493Qmutation.

Interestingly, BA.2.75 is more sensitive to Omi-32 (IGHV-3-33) thanBA.2, with an 8-fold increase in neutralisation titre. The enhancementin activity by Omi-32 is likely due to a stronger interaction of theantibody with the RBD through the G446S mutation (FIG. 19A, Table 22).

To confirm that the change in neutralising activities observed areassociated with alterations in RBD interaction, binding analyses ofselected antibodies to BA.2.75 and BA.2 RBDs were performed by surfaceplasmon resonance (SPR) (FIG. 24 ). Binding of Omi-29 (IGHV3-53) andOmi-36 (IGHV3-66) to BA.2.75 was severely impaired, and Omi-18 andOmi-20 showed 8-fold reductions compared to BA.2. On the other hand, a2-fold increase in binding affinity of Omi-32 was seen for BA.2.75 incomparison with BA.2, in line with the enhanced neutralisation titreobserved.

Escape from Commercial Monoclonals Against BA.2.75

The sensitivity of a panel of mAbs that have been developed astherapeutics against BA.2.75 (FIG. 19B, Table 23) was evaluated. Theneutralisation profiles are in general similar between BA.2.75 and BA.2;however, further to the 6/12 mAbs (REGN10933, ADG10, ADG20, ADG30,Ly-CoV555, Ly-CoV 16) which have already suffered complete loss ofneutralising activity for BA.2, the residual activity of REG10987(Weinreich et al., 2021, “REGN-COV2, a Neutralizing Antibody Cocktail,in Outpatients with Covid-19.” N Engl J Med 384, 238-251) against BA.2was further knocked out for BA.2.75 due to the G446S mutation(Dejnirattisai et al, 2022). For AstraZeneca AZD1061, activity againstBA.2.75 was similar to that against BA.2 (<3-fold reduction); whilst theAZD8895 titre was restored to 0.008 μg/ml for BA.2.75 from 1.333 μg/mlfor BA.2, a 167-fold increase in activity. As a result, AZD7442 (acombination of AZD8895 and AZD1061) (Dong et al., 2021, “Genetic andstructural basis for recognition of SARS-CoV-2 spike protein by atwo-antibody cocktail”. Nature Microbiol. 6, 1233-1244) showed similaractivity against BA.2.75 and BA.2 (2-fold reduction). The results can beexplained by the structure of the ternary complex of the ancestralSARS-CoV-2 RBD/AZD1061/AZD8895 (Dong et al., 2021). G446 has contactswith CDR-L2 Y55 and W56 of AZD1061, G446S mutation will induce stericclashes (FIGS. 21D, E). While CDR-H2 of AZD8895 sits above and makes ahydrogen bond to Q493 of the RBD, an arginine at 493 will severely clashwith CDR-H2 of the mAb (FIGS. 21F, G). The activity of S309 (Sun and Ho,2020, “Emerging antibody-based therapeutics against SARS-CoV-2 duringthe global pandemic.” Antib Ther 3, 246-256) is increased 3-fold forBA.2.75 compared to BA.2, suggesting that the D339H mutation in BA.2.75reduces the impact of the preceding G339D mutation in BA.2 on theactivity of S309. LY-CoV 1404 (bebtelovimab) (Westendorf et al., 2022,“LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.”Cell Rep 39, 110812) is the only mAb where neutralization is fullyretained on all Omicron sublineages.

Escape from Monoclonal Antibodies by BA.2, BA.4 and BA.5 Sublineages

Attrition of mAb activity was also observed with the new BA.2, BA.4 andBA.5 sublineages (including BA.4.6, BA.2.75, BA.2.75.2, BA.2.3.20, BJ.1,BQ.1, BQ.1.1, XBB, XBB.1 and XBB.1.5) (FIG. 34 ), with XBB leading tothe most extreme escape. Activity of all 9 IGHV3-53/66 mAbs wasreduced >100-fold with complete knock out of activity in 5/9 byBA.2.75.2. Only a single mAb, Omi-42 was unaffected by all variants.Omi-42 is unusual as it binds at the back of the left shoulder of theRBD (Nutalai et al., 2022) in a region that has not yet been targetedfor mutation by the set of newly emerging BA.2 variants, perhaps becauseof the relative rarity of antibodies binding in this region.

Further data can be found in Nutalai, et al. (2022) “Potentcross-reactive antibodies following Omicron breakthrough in vaccines”,Cell 185(12), 2116-2131; Huo et al. (2022) “Humoral responses againstSARS-CoV-2 Omicron BA.2.11, BA.2.12.1 and BA.2.13 from vaccine and BA.1serum”, Cell discovery 8, 119; and Huo, et al. (2022) “A delicatebalance between antibody evasion and ACE2 affinity for Omicron BA.2.75”Cell Reports, 42(1). 2023.

Neutralisation of BA.2 Subvariants BA.2.11, BA.2.12 and BA.2.13 byVaccine Serum

The receptor binding capacity of the BA.2 subvariants BA.2.11, BA.2.12and BA.2.13 was also evaluated. A high-resolution crystal structure ofBA.2.12.1 RBD was generated, showing differential sensitivity of newBA.2 subvariants BA.2.11, BA.2.12 and BA.2.13 to serum samples andmonoclonal antibodies (mAbs) compared to BA.2.

Considering the physico-chemical properties of the side chain of residue452, BA.2.13 would be expected to be a relatively modest change; L to Mwill increase the size of the side chain but it remains hydrophobic. Lto Q in BA.2.12.1 introduces some polar character, whilst BA.2.11 is themost radical with L to R introducing a large basic amino acid.

Neutralisation of BA.2 Subvariants BA.2.11, BA.2.12 and BA.2.13 byVaccine Serum

To evaluate the susceptibility of the BA.2 subvariants to neutralisationby immune sera, neutralization assays were performed on pseudotypedlentiviruses expressing the Spike gene of BA.2.11, BA.2.12 and BA.2.13,using a series of serum samples.

Firstly, the neutralisation profile with sera collected 4 weeksfollowing a third dose of the Oxford-AstraZeneca vaccine AZD1222 (n=41)or Pfizer-BioNtech vaccine BNT162b2 (n=18) was observed. No significantloss in neutralisation titre was seen compared to BA.2. In fact, BA.2.13showed a significant increase (1.6-fold, p<0.0001) for AZD1222 vaccinees(FIGS. 27 a, b ). This contrasts with a recent report (Cao, Y., et al.,“BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicroninfection”. Nature, 2022), where sera collected from triple-dosevaccinees (4 weeks following a third dose of the inactivated vaccineCoronaVac or a ZF2001 booster after two doses of CoronaVac) showedsignificant reductions in neutralisation titre for both BA.2.12.1 andBA.2.13 (BA.2.11 was not tested).

Neutralisation of BA.2 Subvariants BA.2.11, BA.2.12 and BA.2.13 by Serumfrom Vaccine Breakthrough BA.1 or BA.2 Infections

Next, the neutralisation profile for serum samples collected fromvaccinees infected with BA.1 were examined. Samples (n=14) were taken≥28 days following symptom onset (median 38 days); all convalescentindividuals had received at least 2 doses of vaccine, 3 of them receiveda third dose of vaccine following Omicron infection. There weresignificant reductions in neutralisation titre for all three variantscompared to BA.2, with the greatest decrease for BA.2.11 (1.6-fold,P=0.0067), followed by BA.2.12.1 (1.4-fold, P=0.0085) and BA.2.13(1.2-fold, P=0.0085) (FIG. 27 c ). Together, these observations suggestthat, in comparison with BA.2, its subvariants are not showing strongerhumoral immune escape in individuals vaccinated with three doses of AZD1222 or BNT162b2. However, for vaccinees who had a BA.1 breakthroughinfection, regardless of the type of vaccine they had received, the BA.2variants are more capable of evading the humoral response, although abroad neutralizing antibody response, with high titres to all thevariants of concern, is induced (Nutalai, R., et al., “Potentcross-reactive antibodies following Omicron breakthrough in vaccines”.Cell, 2022. 185(12): p. 2116-2131 e18). This may indicate the differentselective pressure on BA.2 and its subvariants on a high background ofbreakthrough infection. As antibody titres naturally wane at longer timepoints, people with BA.1 breakthrough infections are expected to be moresusceptible to reinfection with the BA.2 subvariants.

To further elucidate the differential responses between BA.2 and itssubvariants, pseudoviral assays were performed on a panel of potenthuman monoclonal antibodies (mAbs) generated from cases of BA.1breakthrough infection (Nutalai, et al., 2022). (FIG. 29 ). In line withthe structural observation and neutralisation results, the greatestreduction of neutralisation titre was seen for BA.2.11, followed byBA.2.12.1 and BA.2.13, neutralization of BA.2.11 was completely knockedout for 5/27 mAbs (Omi-06, Omi-24, Omi-30, Omi-31 and Omi-34). Theneutralising activity against BA.2.12.1 was also reduced to varyingdegrees for the same set of mAbs, whilst the profiles were largelyunchanged against BA.2.13. Among them, Omi-06 belongs to the IGVH4-4family, and the other four mAbs belong to the IGVH1-69 family. Indeed,previous structural studies predicted Omi-06 and Omi-31 to be sensitiveto the L452R mutation in Delta (Nutalai, et al., 2022). To confirm thatthe differential neutralization effects observed are directlyattributable to the changes in RBD binding, surface plasmon resonance(SPR) was used to compare the binding behaviour of BA.2 and BA.2.12.1RBD, using Omi-06 and Omi-31 as examples. As expected the affinitieswere reduced, for Omi-06, BA.2.12.1 RBD was 15-fold weaker binding thanBA.2 and, strikingly, the binding of BA.2.12.1 RBD to Omi-31 was about1300-fold weaker (FIG. 30 ).

The spike mutations in the BA.2.11, BA.2.12 and BA.2.13 variants couldrender it slightly more transmissible than BA.2. However, compared toBA.2, they do not appear to have acquired greater humoral immune escapein healthy vaccinees who have received three doses of theOxford-AstraZeneca or Pfizer-BioNtech BNT162b2 vaccine. This resultdiffers from that of vaccinees who have received the triple-doseCoronaVac vaccine, for whom significant reductions in neutralisationtitres were observed (Cao, Y., et al., BA.2.12.1, BA.4 and BA.5 escapeantibodies elicited by Omicron infection. Nature, 2022). Nevertheless,significant reductions in neutralisation titres were seen in vaccineeswho had experienced BA.1 breakthrough infections, no matter which typeof vaccine was received, perhaps partly due to partial or completeknock-out of neutralising activity of antibodies belonging to theIGVH1-69 family, many of which are sensitive the mutation at leucine 452of the Spike RBD. This suggests that the continuously evolving Omicronsublineages are able to gain evasion from the humoral immune responsesmounted by BA.1, thus implying that BA.1 Spike or RBD might not be asubstantially better immunogen than that of the ancestral Wuhan strainfor the development of the next-generation SARS-CoV-2 vaccine.

BA.2.12.1 Crystal Structures

The crystal structure of BA.2.12.1 RBD was determined at 2.38 Å as aternary complex with a neutralizing Fab and nanobody (FIGS. 27 h-m ),demonstrating that structural differences are essentially restricted tothe side-chain of residue 452.

Neutralisation of BA.2.75.2 by mAbs Made Following BA.1 Infection

Neutralisation of BA.2.75.2 by a panel of mAbs made following BA.1infection (Nutalai et al., 2022) was investigated. Attrition of mAbactivity was observed against BA.2.75.2 (Table 32a). Activity of all 9IGVH3-53/66 mAbs was reduced >100-fold with complete knock out ofactivity in 4/9 by BA.2.75.2. Only a single mAb, Omi-42 was unaffectedby all variants showing neutralization of the BA.4+14 mutationsdescribed with IC50 of ling/ml. Omi-42 is unusual as it binds at theback of the left shoulder of the RBD (Nutalai et al., 2022) in a regionthat has not yet been targeted for mutation, perhaps because of therelative rarity of antibodies binding in this region.

A panel of mAb that have been developed for clinical use was also tested(Dong et al., 2021; Sun and Ho, 2020; Weinreich et al., 2021; Yuan etal., 2022). Many of these were severely impacted by a number ofvariants. Activity of all mAbs apart from S309 was knocked out by one ormore variants including Ly-CoV 1404 (Westendorf et al., 2022) (see Table32b).

Pfizer BNT162b2 Vaccine Serum Neutralization Titres for BA.2.75.2 andBA.2.3.20.

Neutralization on serum collected 28 days following a third dose ofPfizer BNT162b2 vaccine (Polack et al., 2020) and in cases infected withBA.1, BA.2 of BA.4/5 the characteristics of these subjects are describedin the methods.

Using serum obtained 28 days following BNT162b, infection titres toBA.2.75.2 showed large reductions compared to BA.2 and BA.4, and werethe lowest of all variants tested compared to the ancestral strainVictoria. The reduction in titres to BA.2.75.2 were in contrast toBA.2.75 which showed only a modest reduction compared to BA.2. Therewere also large reductions in titres to BA.2.3.20.

Using serum obtained following BA.1, BA.2 and BA.4/5 infection, therewere similar large reductions in the neutralization titres of BA.2.75.2and BA.2.3.20 compared to BA.4/5. Neutralization of the BA.4+14 RBDmutations described above were also reduced compared to BA.2 and BA.4/5but not a great deal more than BA.2.75.2 indicating a dominant effect ofmutations in BA.2.75.2

Neutralisation of BA4.6 by Serum from Vaccine Breakthrough BA.1 or BA.2Infections

Here, we study the neutralisation profile of BA.4.6 using:Pfizer-BioNtech vaccine serum, BA.1, BA.2 and BA.4/5 vaccinebreakthrough immune serum, as well as panels of monoclonal antibodies.Remarkably, we show further antibody evasion of BA.4.6, providingguidance for vaccine design and the use of therapeutic monoclonals.

To evaluate the antibody evasion capacity of BA.4.6, we constructed apanel of pseudotyped lentiviruses (Di Genova, C., et al., Production,titration, neutralisation and storage of SARS-CoV-2 lentiviralpseudotypes. figshare, 2020.) expressing the S gene from BA.4.6 andother SARS-CoV-2 variants together with early pandemic Wuhan relatedstrain, Victoria, used as a control. Firstly, the neutralisation profilewas examined with sera collected 4 weeks following a third dose of thePfizer-BioNtech vaccine BNT162b2 (n=22). Compared to BA.4/5,neutralisation titres against BA.4.6 were reduced 2-fold (p<0.0001) forBNT162b2 sera (FIG. 28 a ).

The neutralisation profile for serum samples collected from vaccineesinfected with BA.1 were assated. Samples (n=16) were taken ≥28 daysfollowing symptom onset. BA.2 samples (n=23) were taken ≥12 daysfollowing symptom onset or BA.4/5. Samples (n=11; all but onevaccinated) were taken >23 days following symptom onset (FIGS. 28 b-d ).Neutralization titres against BA.4.6 were significantly reduced comparedto BA.4/5 for both breakthrough BA.1 (1.5-fold; P=0.0006) and BA.2(1.2-fold; P=0.0384) serum samples. Notably, BA.4.6 was able toeffectively escape neutralisation by serum samples from BA.1breakthrough infections, showing substantial reduction in titrescompared to BA.1 (4.4-fold; p=0.0001), BA.2 (3-fold; p=0.0009) andBA.4/5 (1.5-fold; p=0.0006). A small non-significant increase inneutralisation titres against BA.4.6 was observed in the BA.4/5breakthrough cohort compared to BA.4/5.

To further characterise the antigenic escape properties of BA.4.6,pseudoviral assays were performed on a panel of potent human mAbsgenerated from BA.1 breakthrough convalescents (Nutalai et al., 2022)(FIG. 28 e ). In general, the neutralisation profiles of BA.4.6 weresimilar to those of BA.4/5. However, the residual activity of Omi-35(IC50=1.687 μg/mL) was further knocked out for BA.4.6, and the potencyof Omi-32 and Omi-33 against BA.4/5 (IC50=0.035 and 0.013 μg/mL,respectively) was completely impaired for BA.4.6. The loss in activityof Omi-32 could be explained by the disrupted interaction between H1 andR346 as illustrated by previous structural analysis (Nutalai et al.,2022).

Neutralisation of BA.4.6, by mAbs in Clinical Use

Finally, neutralisation activities of a number of mAbs in clinical usewas evaluated (FIG. 28 f ). The potency of AZ 1061/cilgavimab againstBA.4/5 was completely knocked out against BA.4.6, leading to a totalloss in activity of AZ7742/Evusheld (a combination of AZ1061/cilgavimaband AZ8895/tixagevimab which is already inactive against BA.4/5). Theactivity of S309/sotrovimab (no longer authorized by the U.S. food anddrug administration FDA for COVID-19 treatment since April 2022 due toits inefficacy against BA.2) was further reduced compared to BA.2 andBA.4/5. This therefore leaves Ly-Cov1404/bebtelovimab the only optionfor treatment of BA.4.6.

In summary, BA.4.6 showed further reduction in neutralisation by serumfrom triple dose Pfizer vaccinees, as well as from BA.1 and BA.2 vaccinebreakthrough convalescents compared to BA.4/5. Notably, BA.4.6 does notseem to more resistant to neutralisation by serum from BA.4/5breakthrough infection compared to other variants. This altogethersuggests that there is a strong likelihood of infection or breakthroughinfection by BA.4.6 unless one has been triply vaccinated and recoveredfrom BA.4/5 infections, which seems to provide some protection againstBA.4.6.

As of September 2022, bivalent booster vaccination, combining theancestral strain with Omicron BA.1 is being rolled out in the UK, andhas been recently authorised by FDA. It remains to be seen how effectivethese bivalent boosters are at preventing BA.4.6 infection. Finally,BA.4.6 has further impaired the activity of Evusheld which remainedactive against BA.4/5; as a result, now only LY-CoV 1404/bebtelovimabretains potency against all circulating SARS-CoV-2 variants.

Systematic Themes in mAb Interactions

Both Omi-3 (a representative of the IGVH3-53 gene family) and AZD8895(IGVH1-58) make contacts with F486. Whilst the F486V mutation has littleeffect on Omi-3 (FIGS. 10F, G, 11F), it seriously reduces theneutralization of AZD8895 and other IGVH1-58 mAbs e.g. Omi-12 (FIGS.10D, E, 11E). It is notable that whereas the numerous Omi seriesantibodies belonging to the closely related IGVH3-53 and IGVH3-66 genefamilies (9/28 in total FIG. 8A Table 21) are almost entirely resilientto the BA.4/5 changes, the large majority of antibodies from these genefamilies elicited against earlier variants are knocked out on BA.1 andBA.2 (Nutalai et al., 2022), consistent with selection of a subset ofantibodies by breakthrough Omicron infection that are insensitive to thefurther BA.4/5 mutations.

The effects on antibodies with broadly similar epitopes can varydramatically, and this is equally true for antibodies which have 452 or486 central to their binding footprint. Thus Omi-31 (IGVH1-69) andOmi-32 (IGVH3-33), both bind in front of the right shoulder with theirCDR-H3 positioned close to 452, whilst the activity of Omi-31 isabolished by L452R (as detailed above), Omi-32 is markedly enhanced(FIGS. 8A, 11A, B). Similarly, Omi-25 and Omi-42 both belong to theIGVH3-9 gene family and their footprints are in the 486 region (FIGS.11C, D). Omi-25 contacts F486 thus neutralization of BA.4/5 isabolished. In contrast Omi-42 does not contact either of the mutationsites and neutralization is fully retained for BA.4/5 (FIGS. 10H, I,11D).

Fine Mapping of RBD Antibody Binding Using Competition Measurements.

A matrix of pairwise BLI measurements were used to map the potent RBDbinding Omicron mAbs and several pre-pandemic mAbs of known bindingposition.

The method yielded a consistent prediction. The mAbs segregate into arestricted set of epitopes, which appear to be subset of the epitopesobserved for the early pandemic virus, and are quite distinct from thefocus seen for Beta. Essentially the antibodies cluster in two regions,one which includes the VH3-53 and VH3-66 type antibodies is towards theback of the neck/left shoulder, extending up to the top of the leftshoulder, whilst the other is on the front of the neck right shoulderregion, spilling towards the S309 known antibody binding site. Thisregion is occupied by the VH1-69 family antibodies, with the exceptionof Omi-2 which is sited within the other cluster. mAb Omi-09 which showsreduced neutralization of Beta and Gamma positions close to residue 484which is mutated from Glu to Lys in Beta/Gamma and Ala in Omicron.VH1-69 mAb Omi-24, 30, 31 and 34, which show reduced neutralization ofDelta are placed close to residue 452 which is mutated from Leu to Argin Delta.

Structures of Anti-Omicron Fab/RBD Complexes

Structural analyses of selected potent Omicron mAbs were performed.Crystal structures were determined for complexes of Omicron BA.1 RBDwith 3 different Fabs: Omi-3, 9 and 12. The complex of Omi-12 was at lowresolution (5.5 Å) and so the structure of the Fab alone was determinedat high resolution and rigid-body fitted to obtain the complexstructure.

Omi-3 belongs to the VH3-53 gene family and demonstrates how this genefamily can be adapted to be broadly neutralising against all majorSARS-CoV-2 variants (but, like all the potent Omicron antibodies it doesnot bind SARS-CoV-1 RBD). A fundamental problem for these antibodies isthat most VoC harbour mutation N501Y, which introduces a steric clashwith the LC CDR1 (L1) capable of abrogating the binding of the largemajority of VH3-53 containing antibodies. However, two mechanisms fordisplacing L1 to avoid this clash have been previously reported(Dejnirattisai et al., 2021b; Liu et al., 2021b). In mAb-222, isolatedfrom individuals infected with early pandemic strains, a proline isinserted at residue 30 which can pack against Tyr-501 without clashes(Dejnirattisai et al., 2021b), allowing it to effectively neutralizeAlpha, Beta and Gamma variants. Beta-27 uses an alternative mechanism,lengthening the HC CDR3 (H3) loop to 11 residues from the usual 9,displacing L1 to produce enough space to allow 501Y to be stabilised bymain chain interactions conferring similar cross-reactivity (Liu et al.,2021b).

Omi-3 uses the same mechanism as Beta-27 for accommodating the N501Ymutation, although the Omi-3 H3 is one residue longer again. OtherVH3-53 Omicron antibodies (Omi-18 and Omi-29) have H3s very similar toBeta-27 and presumably use the same mechanism. This L1 configuration isalso compatible with the Y505H mutation in Omicron. However, neither 222nor Beta-27 can effectively neutralize Omicron and this may be due tospecific features of the H3 loop which makes close contact with theQ493R Omicron mutation.

Omi-9 is a one of three VH3-30 mAbs and binds across the left shoulderof the RBD. Omi-9 shows relatively weak neutralization of Beta and Gamma(FIG. 2 ). Other antibodies with a high degree of sequence similaritybind similarly, with H3 contacting residue 484. Although the Omi-9/BA.1complex is lower resolution (4.2 Å), it is clear that H3 contactsresidue 484 explaining the sensitivity to E484K in Beta and Gamma whilstE484A in Omicron is tolerated.

Omi-12 belongs to the VH1-58 gene family (it is the only member of thisfamily amongst the 28 potent Omicron antibodies). Like Omi-12, severalmembers of this gene family have a glycosylation site at residue 102 ofthe heavy chain CDR3, the role of which is unclear. VH1-58 antibodieselicited during early pandemic or beta virus infection show reducedability to neutralize Omicron e.g. mAb 253, Beta-47 and Known antibody D(AZD8895) show a reduction in activity of Omicron BA.1 vs Victoriarespectively.

In contrast, Omi-12 has adapted and can potently neutralize Omicron andall VoCs (FIGS. 2 A, B). VH1-58 antibodies bind a left shoulder epitope,H3 contacts S477N but a mutation at this position in Iota had no effecton VH1-58 mAb neutralization using a pseudovirus assay.

Additionally, mAb 253 is still able to neutralize Delta despite theT478K mutation. BA.2 with early pandemic mAb 150 (V113-53). Detectableresidual activity was observed with BA.1, BA.1.1 and BA.2 (BA.3 nottested). Two complex structures were obtained in different space groupswhich were very similar and provided 3 independent views of the complex.mAb 150 binds in a pose similar to that observed previously for earlypandemic virus however it is translated and forms looser interactions,consistent with almost complete loss of neutralization activity. Thisshows the dramatic impact of the accommodating mutations found in Omi-3.

Interestingly, in BA.2 the three serine residues mutated in BA.1 RBD:S371L, S373P and S375F in the loop adjacent to the lipid binding pocketare also muted in BA.2 but the mutation at 371 is to a Phe, which meansthat this is likely a single point mutation from early pandemic, whereasthe S317L mutation in BA.1 requires two mutations. BA.2 may thereforehave features common to earlier versions of the Omicron lineage. Inaddition, the various views provided of this part of the structure showthat it adopts a range of different conformations. This is likely due todifferent crystal contacts and reflects flexibility in this loop region.This is likely to have a biological function since the Ser mutationrequired a double codon change and may possibly affect the presentationof the RBDs. Since we have multiple views of this loop in early pandemicvirus, VoC, Omicron BA.1 and BA.2 we can see that flexibility ismaintained across all variants.

Modelling of Effects on Selected Commercial Known Antibodies, EarlyPandemic and Beta mAb for BA.1, BA.1.1 and BA.2 Changes

Known Antibody A (REGN 10987) and B (10933): Known Antibody B (REGN10933) binds the back of the left shoulder and REGN 10987 the rightshoulder. Activity of both is knocked out by the Omicron lineage apartfrom Known Antibody A (REGN 10987) with BA.2. Known Antibody B (REGN10933) H2 contacts residue 493 and since Q493R is present in all Omicronstrains, neutralizing activity to Omicron is universally lost. KnownAntibody A (REGN 10987) H2 contacts residue 446. BA.2 uniquely lacks theG446S mutation thus regn 10987 retains some neutralization capability.

Known Antibody C (AZD1061) & D (AZD8895): Known antibody C (AZD1061) andD (AZD8895) bind the back of the left shoulder and the front of theright shoulder respectively both show reduced neutralization. Knownantibody C (AZD 1061) is still able to neutralize BA.2 and BA.3(˜10-fold reduction) but neutralization of BA.1 is reduced >100-foldcompared to Victoria and BA.1.1>1000-fold compared to Victoria. Knownantibody C (AZD1061) is affected due to contacts with G446S (absent inBA.2 and BA.3) and R346K (BA.1.1) mutations (contacted by L2 and H3).Known antibody D (AZD8895) is a VH1-58 antibody and contacts residues477 (H3) & 493 (H2) and is compromised by the S477N and Q493R mutationsuniversally present in the Omicron lineage. Known Antibody E (AZD7442)(a combination of C and D) maintains some neutralizing activity againstOmicron strains as the sum of its components.

Known Antibodies F, G and H: All of Known Antibodies F, G and H sufferconsiderable loss of activity against Omicron. Activity of KnownAntibodies F and H are completely lost whilst the activity of KnownAntibody G (ADG20) on Omicron is reduced 276-fold

Known Antibodies I and J: Activity of both antibodies on the entireOmicron lineage is knocked out. Known Antibody J (Ly-CoV 16) (VH3-53)makes extensive interactions with N501 and Y505 via L1 and L3 making itsensitive to mutations at these residues. Known Antibody I (Ly-CoV-555)is vulnerable to the E484K mutation in delta but likely tolerates E484Ahowever, it also contacts residue 493, thus the universal

Omicron Q493R mutation will abrogate binding across the board.

Known Antibody K (S309): Known Antibody K (S309) retains reasonableactivity across the Omicron lineage. S309 binds on the right flank withH3 contacting G339 and N343 glycans the latter close to the Serine 371,373 and 375 mutations. The S371F mutation in BA.2 as opposed to S371L)may affect binding resulting in the slightly weaker activity with thisvirus.

Structure of BA.2 RBD and ACE2 Affinity

The affinity of Omicron BA.1, BA.1.1, BA.2 and BA.3 RBDs for ACE2 wasmeasured by SPR and BLI. The affinity of BA.1 was on a par with that ofthe early virus, 8 nM and 7 nM respectively (binding affinities forOmicron RBDs shown in Tables 14 and 18), implying that the increasedaffinity imparted by S477N, Q498R and N501Y is counter balanced by othermutations in the ACE2 footprint. The affinity of BA.2 was slightlyincreased compared to early virus (˜1.5-fold× and Y nM respectively). Onthe basis of earlier measurements of the contributions of individualmutations to binding affinity G496S and the triple-mutation S371L, S373Pand S375F reduce binding by 2-fold and 2.2-fold respectively whereasBA.2 lacks G496S and has S371F. This may account for some of thedifference but more likely the mutations in BA.2 on the edge of the ACE2footprint may enhance binding. This is confirmed by the structure of theBA.2/ACE2.

BA.4/5 RBD and ACE2 Affinity

The affinity of BA.4/5 RBD for ACE2 was also measured by SPR (FIGS.12A-D). The affinity of BA.4/5 RBD was increased compared to theancestral virus (Wuhan), BA.1 and BA.2 (approximately 3-fold, 3-fold and2-fold, respectively (BA.4/5/ACE2 KD=2.4 nM) (Dejnirattisai et al.,2022; Nutalai et al., 2022), which is mainly attributed to an increasein binding half-life. Modelling of the ACE2/RBD complex suggests thatthe bulk of this effect comes from the electrostatic complemantarybetween ACE2 and the RBD contributed by the L452R mutation (FIGS.12E-G).

BA.2.75 RBD and ACE2 Affinity

Surface plasmon resonance (SPR) was also used to characterise theinteraction between ACE2 and the BA.2.75 RBD. The off-rate was veryslow, leading to a sub-nanomolar affinity (BA.2.75/ACE2 KD=0.45 nM)(FIGS. 18A, B). This represents a considerable increase in affinitycompared to BA.2 (9-fold) (FIG. 18C), and even tighter than BA.4/5(5-fold) (FIG. 18D), which binds to ACE2 with higher affinity than BA.2(Tuekprakhon et al., 2022). BA.2.75 was found to be the strongest ACE2binder amongst all SARS-CoV-2 VoC, including Alpha (Alpha/ACE2 KD=1.5nM; FIG. 18E), and the first SARS-CoV-2 VoC to have a sub-nanomolaraffinity.

BA.2+N460K RBD could not be expressed, but the binding affinity ofBA.2+R493Q RBD to ACE2 (FIG. 18F) was also measured (KD=0.55 nM). Thisconfirms that the R493Q reversion mutation contributes to the highaffinity of BA.2.75 RBD.

Impact of Mutations in BA.2.75

The constellation of mutations in BA.2.75 compared to BA.2 have opposingeffects on neutralization. The reversion mutation R493Q makes the viruseasier to neutralize using vaccine serum (the vaccine contains Q493),whilst N460K reduces neutralization titres to a greater extent whenexpressed in isolation compared to the combination of mutations seen inBA.2.75. N460K is a novel substitution that has not appeared inpreceding variants of SARS-CoV-2. This mutation was introduced into theBA.2 backbone and its impact on neutralisation by BNT162b2 serum wasevaluated. Strikingly, BA.2+N460K titres were reduced 3.1-fold comparedto BA.2, greater than the reduction seen with BA.2.75, and on a par withthe reduction seen for BA.4/5.

Using a panel of potent mAbs derived from vaccinated individuals whosuffered BA.1 vaccine breakthrough infection, it was shown that theactivity of a number of mAbs belonging to the IGHV3-53/66 family arereduced or knocked out against BA.2.75. IGHV3-53/66 are the mostfrequently isolated mAbs in SARS-CoV-2, and bind an epitope on the‘neck’. IGHV53/66 thus forms a major public antibody response and it isno surprise that the virus has evolved to escape this response.

Although BA.2+N460K RBD could not be expressed, a previous study usingyeast display showed N460K can enhance RBD binding for ACE2, an effectsimilar to that seen with the N501Y mutation first described in Alpha(Zahradnik et al., 2021). Thus, N460K can both enhance antibody escapeand increase receptor binding affinity.

Interestingly, BA.2.75 has also acquired the R493Q reversion (Q493R wasacquired in BA.1 and present in all other Omicron sublineages exceptBA.4/5). BA.2.75 RBD was able to bind ACE2 with 9-fold higher affinitythan BA.2 and more tightly than BA.4/5 (Dejnirattisai et al., 2022;Tuekprakhon et al., 2022). This is partly contributed by the R493Qmutation. BA.2.75 RBD has the highest receptor binding affinity amongall SARS-CoV-2 variants measured to date.

These data suggest there may be a fine balance between antibody escapeand ACE2 receptor affinity. Mutations in BA.2.75 lead to a reduction inneutralization titres of vaccine serum compared to BA.2. IndividualBA.2.75 mutations can cause greater reduction in neutralization titrescompared to the full BA.2.75 S sequence, but these are balanced by theR393Q reversion mutation, which may have been selected to increaseaffinity to ACE2 and increase the transmissibility of BA.2.75.

BA.2.11, BA.2.12 and BA.2.13 RBD and ACE2 Affinity

To evaluate the possible change in transmissibility of the BA.2subvariants SPR experiments were performed to analyse their RBD bindingto ACE2 (FIGS. 27 d-g ). The three RBD variants have an affinity ofapproximately 3 nM for ACE2, slightly higher than that of BA.2 RBD (KD=4nM) as previously reported (Nutalai et al., 2022). Modelling of theACE2/RBD complex suggests that this increase in affinity may result fromslightly improved complementarity between ACE2 and the RBD contributedby the mutation at leucine 452. Therefore, these variants might have asubtle advantage in transmission over BA.2.

Antigenic Cartography of BA.3 and BA.4/5

The neutralization data above has been used to place BA.3 and BA.4/5 onan antigenic map. The method used for analysis of the Delta and Omicronvariants was repeated (Liu et al., 2021, “Reduced neutralization ofSARS-CoV-2 B.1.617 by vaccine and convalescent serum”. Cell 184,4220-4236 e4213), where individual viruses were independently modelledallowing for serum specific scaling of the responses. The measured andmodelled responses are shown in FIG. 13A (with 1551 observations and 340parameters the residual error is 23%). The results are best visualizedin three dimensions (see 2D projections in FIG. 13B). This shows, asexpected, that the Omicron sub-lineages are clustered together but wellseparated from early pandemic virus and earlier VoC. Amongst the Omicroncluster BA.4/5 is the most distant from the pre-Omicron viruses.

Antigenic Cartography of BA.2.75

Neutralization of BA.2.75 was tested using serum from individualspreviously infected during the course of the pandemic. These includedserum obtained early in the pandemic (before the emergence of Alpha)together with serum obtained following Alpha, Beta, Gamma, Delta, BA.1and BA.2 infection (FIG. 25 ). As expected, BA.2.75 neutralizationtitres were lower than the homologous infecting strain (e.g. Alpha serumon Alpha virus). Most striking however was the complete loss of BA.2.75neutralization using Delta serum (zero samples achieved 50%neutralization at 1/20 dilution). However, titres to BA.2.75 were muchhigher in cases who had been vaccinated before or after Delta infection.

These data were used to place BA.2.75 onto a three dimensional antigenicmap using the method previously reported in Tuekprakhon et al., 2022(FIGS. 22A, B). Initially all VoC were included (FIG. 22A); this showedthat BA.2.75 was grouped with the other Omicron viruses, whichsegregated into one hemisphere of the 3D plot. BA.2.75 appeared wellseparated from other Omicron sub-lineages and especially from BA.4/5. Itis also notable that BA.2.75 and Delta are diametrically opposed in thediagram, emphasising the antigenic distance between these two viruses.Since the data are higher dimensional, the 3D projection is likely todistort the true distances and so were calculated for only the Omicronand early pandemic viruses (but retaining the full serology informationfor each of these). The results are shown in FIG. 22B and recapitulatethe major features of the full plot, but allow the Omicron sublineagesto distribute more broadly in 3D space. Remarkably, if the clusteredearly pandemic and BA.2/BA.3 pairs are merged then the points aredistributed as a trigonal bi-pyramid maximising their separation,consistent with antigenic escape being a significant factor in theirevolution.

Example 3. Examples of Antibodies that May be Created by Swapping theLight Chain Between Antibodies Derived from the Same Heavy Chain V-Gene

As discussed in the detailed description above, antibodies derived fromthe same heavy chain V-gene may swap light chains to result in anantibody comprising the heavy chain variable region of a first antibodyand a light chain variable region of a second antibody, and such newantibodies may have improved neutralisation and/or other characteristicswhen compared to the ‘parent’ antibodies.

Tables 4 to 12 provide examples of such antibodies that may be creasedby swapping the light chain between antibodies derived from the sameheavy chain V-gene. Table 17 provides information as to the heavy chainand light chain V-genes from which the 28 Omicron-specific mAbs arederived, together with their specificity to the RBD or NTD of the spikeprotein of SARS-CoV-2.

Example 4. Materials and Methods Viral Stocks

SARS-CoV-2/human/AUS/VIC01/2020 (Caly et al, 2020), Alpha and Beta wereprovided by Public Health England, Gamma cultured from a throat swabfrom Brazil, Delta was a gift from Wendy Barclay and Thushan de Silva,from the UK G2P genotype to phenotype consortium and Omicron was grownfrom a positive throat swab (IRAS Project ID: 269573, Ethics Ref:19/NW/0730. Briefly, VeroE6/TMPRSS2 cells (NIBSC) were maintained inDulbecco's Modified Eagle Medium (DMEM) high glucose supplemented with1% fetal bovine serum, 2 mM Glutamax, 100 IU/ml penicillin-streptomycinand 2.5 ug/ml amphotericin B, at 37° C. in the presence of 5% CO2 beforeinoculation with 200 ul of swab fluid. Cells were further maintained at37° C. with daily observations for cytopathic effect (CPE). Viruscontaining supernatant were clarified at 80% CPE by centrifugation at3,000 r.p.m. at 4° C. before being stored at −80° C. in single-usealiquots. Viral titres were determined by a focus-forming assay on VeroCCL-81 cells (ATCC).

Sequencing of the Omicron isolate shows the expected consensus S genechanges (A67V, Δ69-70, T95I, G142D/Δ143-145, Δ211/L212I, ins214EPE,G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A,Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H,N764K, D796Y, N856K, Q954H, N969K, L981F), an intact furin cleavage siteand a single additional mutation A701V.

Cells were infected with the SARS-CoV-2 virus using an MOI of 0.0001.

Virus containing supernatant were harvested at 80% CPE and spun at 3000rpm at 4° C. before storage at −80° C. Viral titres were determined by afocus-forming assay on Vero cells. Victoria passage 5, Alpha passage 2and Beta passage 4 stocks Gamma passage 1, Delta passage 3 and Omicronpassage 1 were sequenced to verify that they contained the expectedspike protein sequence and no changes to the furin cleavage sites.

Bacterial Strains and Cell Culture

Vero (ATCC CCL-81) and VeroE6/TMPRSS2 cells were cultured at 37° C. inDulbecco's Modified Eagle medium (DMEM) high glucose (Sigma-Aldrich)supplemented with 10% fetal bovine serum (FBS), 2 mM GlutaMAX (Gibco,35050061) and 100 U/ml of penicillin-streptomycin. Human mAbs wereexpressed in HEK293T cells cultured in UltraDOMA PF Protein-free Medium(Cat #12-727F, LONZA) at 37° C. with 5% CO₂. HEK293T (ATCC CRL-11268)cells were cultured in DMEM high glucose (Sigma-Aldrich) supplementedwith 10% FBS, 1% 100× Mem Neaa (Gibco) and 1% 100× L-Glutamine (Gibco)at 37° C. with 5% CO₂. To express RBD, RBD variants and ACE2, HEK293Tcells were cultured in DMEM high glucose (Sigma) supplemented with 2%FBS, 1% 100× Mem Neaa and 1% 100× L-Glutamine at 37° C. fortransfection. Omicron RBD and human mAbs were also expressed in HEK293T(ATCC CRL-11268) cells cultured in FreeStyle 293 Expression Medium(ThermoFisher, 12338018) at 37° C. with 5% CO₂ . E. coli DH5a bacteriawere used for transformation and large-scale preparation of plasmids. Asingle colony was picked and cultured in LB broth at 37° C. at 200 rpmin a shaker overnight.

Sera from Pfizer Vaccinees

Pfizer vaccine serum was obtained from volunteers who had receivedeither one or two doses of the BNT162b2 vaccine. Vaccinees were HealthCare Workers, based at Oxford University Hospitals NHS Foundation Trust,not known to have prior infection with SARS-CoV-2 and were enrolled inthe OPTIC Study as part of the Oxford Translational GastrointestinalUnit GI Biobank Study 16/YH/0247 [research ethics committee (REC) atYorkshire & The Humber—Sheffield] which has been amended for thispurpose on 8 Jun. 2020. The study was conducted according to theprinciples of the Declaration of Helsinki (2008) and the InternationalConference on Harmonization (ICH) Good Clinical Practice (GCP)guidelines. Written informed consent was obtained for all participantsenrolled in the study. Participants were studied after receiving twodoses of, and were sampled approximately 28 days (range 25-38), 180 days(range 178-221) and 270 days (range 243-273) after receiving two dosesof Pfizer/BioNtech BNT162b2 mRNA Vaccine, 30 micrograms, administeredintramuscularly after dilution (0.3 mL each), 17-28 days apart, thenapproximately 28 days (range 25-56) after receiving a third “boosterdose of BNT162B2 vaccine. The mean age of vaccinees was 37 years (range22-66), 21 male and 35 female.

Plasma from Early Pandemic and Alpha Cases

Participants from the first wave of SARS-CoV2 in the U.K. and thosesequence confirmed with B.1.1.7 lineage in December 2020 and February2021 were recruited through three studies: Sepsis Immunomics [Oxford RECC, reference:19/SC/0296]), ISARIC/WHO Clinical Characterisation Protocolfor Severe Emerging Infections [Oxford REC C, reference 13/SC/0149] andthe Gastro-intestinal illness in Oxford: COVID sub study [Sheffield REC,reference: 16/YH/0247]. Diagnosis was confirmed through reporting ofsymptoms consistent with COVID-19 and a test positive for SARS-CoV-2using reverse transcriptase polymerase chain reaction (RT-PCR) from anupper respiratory tract (nose/throat) swab tested in accreditedlaboratories. A blood sample was taken following consent at least 14days after symptom onset. Clinical information including severity ofdisease (mild, severe or critical infection according to recommendationsfrom the World Health Organisation) and times between symptom onset andsampling and age of participant was captured for all individuals at thetime of sampling. Following heat inactivation of plasma/serum samplesthey were aliquoted so that no more than 3 freeze thaw cycles wereperformed for data generation.

Sera from Beta, Gamma and Delta and BA.1 Infected Cases

Beta and Delta samples from UK infected cases were collected under the“Innate and adaptive immunity against SARS-CoV-2 in healthcare workerfamily and household members” protocol affiliated to theGastro-intestinal illness in Oxford: COVID sub study discussed above andapproved by the University of Oxford Central University Research EthicsCommittee. All individuals had sequence confirmed Beta/Delta infectionor PCR-confirmed symptomatic disease occurring whilst in isolation andin direct contact with Beta/Delta sequence-confirmed cases. AdditionalBeta infected serum (sequence confirmed) was obtained from South Africa.At the time of swab collection patients signed an informed consent toconsent for the collection of data and serial blood samples. The studywas approved by the Human Research Ethics Committee of the University ofthe Witwatersrand (reference number 200313) and conducted in accordancewith Good Clinical Practice guidelines. Gamma samples were provided bythe International Reference Laboratory for Coronavirus at FIOCRUZ (WHO)as part of the national surveillance for coronavirus and had theapproval of the FIOCRUZ ethical committee (CEP 4.128.241) tocontinuously receive and analyse samples of COVID-19 suspected cases forvirological surveillance. Clinical samples were shared with OxfordUniversity, UK under the MTA IOC FIOCRUZ 21-02.

Sera from BA.1 Infected Cases, Study Subjects

Following informed consent, individuals with omicron BA.1 wereco-enrolled into the ISARIC/WHO Clinical Characterisation Protocol forSevere Emerging Infections [Oxford REC C, reference 13/SC/0149] and the“Innate and adaptive immunity against SARS-CoV-2 in healthcare workerfamily and household members” protocol affiliated to theGastro-intestinal illness in Oxford: COVID sub study [Sheffield REC,reference: 16/YH/0247] further approved by the University of OxfordCentral University Research Ethics Committee. Diagnosis was confirmedthrough reporting of symptoms consistent with COVID-19 or a positivecontact of a known Omicron case, and a test positive for SARS-CoV-2using reverse transcriptase polymerase chain reaction (RT-PCR) from anupper respiratory tract (nose/throat) swab tested in accreditedlaboratories and lineage sequence confirmed through national referencelaboratories. A blood sample was taken following consent at least 10days after PCR test confirmation. Clinical information includingseverity of disease (mild, severe or critical infection according torecommendations from the World Health Organisation) and times betweensymptom onset and sampling and age of participant was captured for allindividuals at the time of sampling.

AstraZeneca-Oxford Vaccine Study Procedures and Sample Processing

Full details of the randomized controlled trial of ChAdOx1 nCoV-19(AZD1222), were previously published (PMID: 33220855/PMID: 32702298).These studies were registered at ISRCTN (15281137 and 89951424) andClinicalTrials.gov (NCT04324606 and NCT04400838). A copy of theprotocols was included in previous publications (Folegatti et al., 2020,Lancet 396, 467-478).

Data from vaccinated volunteers who received two vaccinations areincluded in the Examples. Vaccine doses were either 5×10¹⁰ viralparticles (standard dose; SD/SD cohort n=21) or half dose as their firstdose (low dose) and a standard dose as their second dose (LD/SD cohortn=4). The interval between first and second dose was in the range of8-14 weeks. Blood samples were collected and serum separated on the dayof vaccination and on pre-specified days after vaccination e.g. 14 and28 days after boost.

Focus Reduction Neutralization Assay (FRNT)

The neutralization potential of Ab was measured using a Focus ReductionNeutralization Test (FRNT), where the reduction in the number of theinfected foci is compared to a negative control well without antibody.Briefly, serially diluted Ab or plasma was mixed with SARS-CoV-2 strainsand incubated for 1 hr at 37° C. The mixtures were then transferred to96-well, cell culture-treated, flat-bottom microplates containingconfluent Vero cell monolayers in duplicate and incubated for a further2 hrs followed by the addition of 1.5% semi-solid carboxymethylcellulose (CMC) overlay medium to each well to limit virus diffusion. Afocus forming assay was then performed by staining Vero cells with humananti-NP mAb (mAb206) followed by peroxidase-conjugated goat anti-humanIgG (A0170; Sigma). Finally, the foci (infected cells) approximately 100per well in the absence of antibodies, were visualized by addingTrueBlue Peroxidase Substrate. Virus-infected cell foci were counted onthe classic AID EliSpot reader using AID ELISpot software. Thepercentage of focus reduction was calculated and IC₅₀ was determinedusing the probit program from the SPSS package.

Plasmid Construction and Pseudo Typed Lentiviral Particles Production

Pseudotyped lentivirus expressing SARS-CoV-2 S proteins from ancestralstrain (Victoria, S247R), BA.1, BA.1.1, and BA.2 were constructed asdescribed before (Nie, Jianhui, et al. “Establishment and validation ofa pseudovirus neutralization assay for SARS-CoV-2.” Emerging microbes &infections 9.1 (2020): 680-686., Liu, Chang, et al. “Reducedneutralization of SARS-CoV-2 B. 1.617 by vaccine and convalescentserum.” Cell 184.16 (2021): 4220-4236), with some modifications.Briefly, synthetic codon-optimized SARS-CoV-2 BA.1 and BA.2 were customsynthesized by GeneArt (Thermo Fisher Scientific GENEART). The insertfragments and pcDNA3.1 vector were cloned by using Gibson assembly.Victoria (S247R) construct is as previously described in Liu, Chang, etal. “Reduced neutralization of SARS-CoV-2 B. 1.617 by vaccine andconvalescent serum.” Cell 184.16 (2021): 4220-4236. To construct BA.1.1,mutagenic primers of R346K (R346K_F5′-GTGTTCAATGCCACCAAATTCGCCAGCGTGTAC-3′ and R346KR5′-GTACACGCTGGCGAATTTGGTGGCATTGAACAC-3′) were PCR amplified by usingBA.1 construct as a template, together with two primers of pcDNA3.1vector (pcDNA3.1_BamHI_F 5′-GGATCCATGTTCCTGCTGACCACCAAGAG-3′ andpcDNA3.1_Tag_S_EcoRI_R5′-GAATTCTCACTTCTCGAACTGAGGGTGGC-3′), purified byusing QIAquick Gel Extraction Kit (QIAGEN) and followed by Gibsonassembly. All constructs were verified by Sanger sequencing afterplasmid isolation using QIAGEN Miniprep kit (QIAGEN).

A similar strategy was applied for BA.3 and BA.4/5, briefly, BA.3mutations were constructed using the combination fragments from BA.1 andBA.2. The resulting mutations are as follows. The resulting mutationsare as follows, A67V, Δ69-70, T95I, G142D, Δ143-145, Δ211/L212I, G339D,S371F, S373P, S375F, D405N, K417N, N440K, G446S, S477N, T478K, E484A,Q493R, Q498R, N501Y, Y505H, D614G, H655Y, N679K, P681H, N764K, D796Y,Q954H, and N969K. Although BA.4/5 S protein shared some amino acidmutations with BA.2 (Nutalai et al., 2022), to generate BA.4/5 mutationswere added 469-70, L452R, F486V, and R498Q. The resulting Sgene-carrying pcDNA3.1 was used for generating pseudoviral particlestogether with the lentiviral packaging vector and transfer vectorencoding luciferase reporter. Integrity of constructs was sequenceconfirmed.

The same method was also used to construct BA.2.12.1, and BA.2.75, byadding more mutations into the BA.2 construct. To generate BA.2.75,K147E, W152R, F157L, 1210V, G275S, G446S and N460K were added into aBA.2 backbone. 339D was also changed in BA.2 S into 339H, and 493R wasreversed in BA.2 to 493Q as in the ancestral strain. To test singlemutation impact, D339H, G446S, N460K and R493Q were introducedindividually into a BA.2 backbone. The resulting pcDNA3.1 plasmidcarrying S gene was used for generating pseudoviral particles togetherwith the lentiviral packaging vector and transfer vector encoding a

Pseudoviral Neutralization Test

The details of pseudoviral neutralization test were described previously(Liu, Chang, et al. “Reduced neutralization of SARS-CoV-2 B. 1.617 byvaccine and convalescent serum.” Cell 184.16 (2021): 4220-4236) withsome modifications. Briefly, the neutralizing activity of potentmonoclonal antibodies (mAbs) generated from donors who had recoveredfrom Omicron- and Beta-infection as well as those who were infectedduring the early pandemic in UK were performed against Victoria,Omicron-BA.1, BA.1.1, BA.2, BA.2.11, BA.2.12.1, BA.2.13, BA.3, BA.4.6,BA.4/5, BA.2.75 and BA.2+N460K. A four-fold serial dilution of each mAbwas incubated with pseudoviral particles at 37° C., 5% CO2 for 1 hr. Thestable HEK293T/17 cells expressing human ACE2 were then added to themixture at 1.5×104 cells/well. At 48 hr. post transduction, culturesupernatants were removed and 50 μL of 1:2 Bright-Glo™ Luciferase assaysystem (Promega, USA) in lx PBS was added to each well. The reaction wasincubated at room temperature for 5 mins and the firefly luciferaseactivity was measured using CLARIOstar® (BMG Labtech, Ortenberg,Germany). The percentage of mAb neutralization was calculated relativeto the control. Probit analysis was used to estimate the value ofdilution that inhibits half of the maximum pseudotyped lentivirusinfection (PVNT50).

To determine the neutralizing activity of convalescent plasma/serumsamples or vaccine sera, 3-fold serial dilutions of samples wereincubated with the pseudoviral particles for 1 hr and the same strategyas mAb was applied.

DNA Manipulations

Cloning was done by using a restriction-free approach (Peleg and Unger,2014). Mutagenic megaprimers were PCR amplified (KAPA HiFi HotStartReadyMix, Roche, Switzerland, cat. KK3605), purified by usingNucleoSpin® Gel and PCR Clean-up kit (Nacherey-Nagel, Germany, REF740609.50) and cloned into pJYDC1 (Adgene ID: 162458) (Zahradnik et al.,2021a). Parental pJYDC1 molecules were cleaved by DpnI treatment (1 h,NEB, USA, cat. R0176) and the reaction mixture was electroporated intoE. coli Cloni® 10G cells (Lucigen, USA). The correctness of mutagenesiswas verified by sequencing.

Cloning of Spike and RBD

Expression plasmids of and Omicron BA.1 spike and RBD of BA.1 and BA.2were constructed encoding for human colon-optimized sequences from BA.1.(EPI_ISL_6640917) and BA.2. (EPI_ISL_6795834.2). The constructs ofWild-type and BA.1 Spike and RBD plasmids are the same as previouslydescribed (Dejnirattisai, Wanwisa, et al. “The antigenic anatomy ofSARS-CoV-2 receptor binding domain.” Cell 184.8 (2021): 2183-2200). Asynthetic codon-optimized RBD fragment of BA.2 was used as a templateand construct was amplified by PCR and cloned into pNEO rector aspreviously described (Dejnirattisai et al., 2021a; Supasa et al., 2021;Zhou et al., 2021). The construct was verified by Sanger sequencing.

To generate His-tagged constructs of BA.4/'S RBD, site-directed PCRmutagenesis was performed using the BA.2 RBD construct as the template(Nutalai et al., 2022), with the introduction of L452R, F486V and R493Qmutations. The gene fragment was amplified with pNeoRBD333Omi|F(5′-GGTTGCGTAGCTCAAACCGGTCATCACCATCACCATCACACC AATCTGTGCCCTTTCGAC-3′)and pNeoRBD333_R (5′-GTGATGGTGGTGCTTGGTACCT TATTACTTCTTGCCGCACACGGTAGC-3′), and cloned into the pNeo vector (Supasa et al.,2021, “Reduced neutralization of SARS-CoV-2B.1.1.7 variant byconvalescent and vaccine sera”. Cell 184, 2201-2211 e2207). To generatethe BA.4/5 RBD construct containing a BAP-His tag, the gene fragment wasamplified with RBD333_F (5′-GCGTAGCTGAAACCGGCACCAATCTGTGC CCTTTCGAC-3′)and RBD333_BAP_R (5′-GTCATTCAGCAAGCTCTTCTTGCCGCACACGG TAGC-3′), andcloned into the pOPINTTGneo-BAP vector (Huo et al., 2020, “Neutralizingnanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2”.Nature structural & molecular biology 27, 846-854). Cloning wasperformed using the ClonExpress II One Step Cloning Kit (Vazyme). The.Constructs were verified by Sanger sequencing after plasmid isolationusing QIAGEN Miniprep kit (QIAGEN).

To generate the BA.2.75 RBD construct, site-directed PCR mutagenesis wasperformed using the BA.2 Spike constrict as the template (Nutalai etal., 2022), with the introduction of D339H, G446S, N460K and R493Qmutations suing primers listed in FIG. 26 ; the gene fragment wasamplified with D339H_pNeoF and RBD333_BAP_R (FIG. 26 ), and cloned intothe pOPINTTGneo-BAP vector (Huo et al., 2020 “Neutralizing nanobodiesbind SARS-CoV-2 spike RBD and block interaction with ACE2,” Naturestructural molecular biology 27, 816-854). To generate the BA.2+R493QRBD construct, site-directed PCR mutagenesis was performed using theBA.2 Spike construct as the template, with the introduction of the R493Qmutation using primers listed in FIG. 26 ; the gene fragment wasamplified with pNeoRBD333Omi_F and BD333_BAP_R, and cloned into the pNeovector (Supasa et al., 2021 “Reduced neutralization of SARS-CoV-2B.1.1.7 variant by convalescent and vaccine sera.” Cell 184, 2201-2211e2207). Cloning was performed using the ClonExpress II One Step CloningKit (Vazyme). The Constructs were verified by Sanger sequencing afterplasmid isolation using QIAGEN Miniprep kit (QIAGEN).

Production of RBDs

Plasmids encoding RBDs were transfected into Expi293F™ Cells(ThermoFisher) by PEI, cultured in FreeStyle™ 293 Expression Medium(ThermoFisher) at 30° C. with 8% CO2 for 4 days. To express biotinylatedRBDs, the RBD-BAP plasmid was co-transfected with pDisplay-BirA-ER(Addgene plasmid 20856; coding for an ER-localized biotin ligase), inthe presence of 0.8 mM D-biotin (Sigma-Aldrich).

Production of BA.2.75 RBDs

Plasmids encoding RBDs were transfected into Expi293F™ Cells(ThermoFisher) by PEI, cultured in FreeStyle™ 293 Expression Medium(ThermoFisher) at 37° C. for 1 day followed by 30° C. for 3 days with 8%CO2. To express biotinylated RBDs, the RBD-BAP plasmid wasco-transfected with pDisplay-BirA-ER (Addgene plasmid 20856; coding foran ER-localized biotin ligase), in the presence of 0.8 mM D-biotin(Sigma-Aldrich). The conditioned medium was diluted 1:2 into bindingbuffer (50 mM sodium phosphate, 500 mM sodium chloride, pH 8.0). RBDswere purified with a 5 mL HisTrap nickel column (GE Healthcare) throughHis-tag binding, followed by a Superdex 75 10/300 GL gel filtrationcolumn (GE Healthcare) in 10 mM HEPES and 150 mM sodium chloride.

Protein Production

Protein expression and purification were conducted as describedpreviously (Dejnirattisai et al., 2021a; Zhou et al., 2020). Briefly,plasmids encoding proteins were transiently expressed in HEK293T (ATCCCRL-11268) cells. The conditioned medium was concentrated using aQuixStand benchtop system. His-tagged Omicron RBD were purified with a 5mL HisTrap nickel column (GE Healthcare) and further polished using aSuperdex 75 HiLoad 16/60 gel filtration column (GE Healthcare).Twin-strep tagged Omicron spike was purified with Strep-Tactin XT resin(IBA lifesciences). ˜4 mg of ACE2 was mixed with homemade His-tagged 3Cprotease and DTT (final concentration 1 mM). After incubated at 4° C.for one day, the sample was flown through a 5 mL HisTrap nickel column(GE Healthcare). His-tagged proteins were removed by the nickel columnand purified ACE2 was harvested and concentrated.

IgG mAbs and Fab Purification

To purify full length IgG mAbs, supernatants of mAb expression werecollected and filtered by a vacuum filter system and loaded on proteinA/G beads over night at 4° C. Beads were washed with PBS three times and0.1 M glycine pH 2.7 was used to elute IgG. The eluate was neutralizedwith Tris-HCl pH 8 buffer to make the final pH=7. The IgG concentrationwas determined by spectro-photometry and buffered exchanged into PBS. Toexpress and purify Fabs 158 and EY6A, heavy chain and light chainexpression plasmids of Fab were co-transfected into HEK293T cells byPEI. After cells cultured for 5 days at 37° C. with 5% CO2, culturesupernatant was harvested and filtered using a 0.22 mm polyethersulfonefilter. Fab 158 was purified using Strep-Tactin XT resin (IBAlifesciences) and Fab EY6A was purified with Ni-NTA column (GEHealthCare) and a Superdex 75 HiLoad 16/60 gel filtration column (GEHealthcare). AstraZeneca and Regeneron antibodies were provided byAstraZeneca, Vir, Lilly and Adagio antibodies were provided by Adagio.For the antibodies heavy and light chains of the indicated antibodieswere transiently transfected into 293Y cells and antibody purified fromsupernatant on protein A. Fab fragments of 58 and beta-55 were digestedfrom purified IgGs with papain using a Pierce Fab Preparation Kit(Thermo Fisher), following the manufacturer's protocol.

Surface Plasmon Resonance

The surface plasmon resonance experiments were performed using a BiacoreT200 (GE Healthcare). All assays were performed with a running buffer ofHBS-EP (Cytiva) at 25° C.

To determine the binding kinetics between the SARS-CoV-2 RBDs andACE2/monoclonal antibody (mAb), a Protein A sensor chip (Cytiva) wasused. ACE2-Fc ormAb was immobilised onto the sample flow cell of thesensor chip. The reference flow cell was left blank. RBD was injectedover the two flow cells at a range of five concentrations prepared byserial twofold dilutions, at a flow rate of 30 μl min⁻¹ using asingle-cycle kinetics programme Running buffer was also injected usingthe same programme for background subtraction. All data were fitted to a1:1 binding model using Biacore T200 Evaluation Software 3.1.

To determine the binding kinetics between the SARS-CoV-2 Spikes andACE2, a CM5 sensor chip was used. The sensor chip was firstly activatedby an injection of equal volume mix of EDC and NHS (Cytiva) at 20 uL/minfor 300 s, followed by an injection of Spike sample at 20 ug/mL in 10 mMsodium acetate pH 5.0 (Cytiva) onto the sample flow cell of the sensorchip at 10 uL/min, and finally with an injection of 1.0 MEthanolamine-HCl, pH 8.5 (Cytiva) at 20 uL/min for 180 s. The referenceflow cell was left blank. ACE2 was injected over the two flow cells at arange of five concentrations prepared by serial twofold dilutions, at aflow rate of 30 μl min⁻¹ using a single-cycle kinetics programme Runningbuffer was also injected using the same programme for backgroundsubtraction.

All data were fitted to a 1:1 binding model using Biacore T200Evaluation Software 3.1. To determine the binding kinetics between theRBDs and mAb Omi-32/Omi-42, a Biotin CAPture Kit (Cytiva) was used.Biotinylated RBD was immobilised onto the sample flow cell of the sensorchip. The reference flow cell was left blank. The mAb Fab was injectedover the two flow cells at a range of five concentrations prepared byserial two-fold dilutions, at a flow rate of 30 μl min-1 using asingle-cycle kinetics programme Running buffer was also injected usingthe same programme for background subtraction. All data were fitted to a1:1 binding model using Biacore T200 Evaluation Software 3.1.

To determine the binding affinity of BA.4/5 RBD and mAb Omi-12, aProtein A sensor chip (Cytiva) was used. The Ig Omi-12 was immobilisedonto the sample flow cell of the sensor chip. The reference flow cellwas left blank. RBD was injected over the two flow cells at a range ofseven concentrations prepared by serial twofold dilutions, at a flowrate of 30 μl min-1. Running buffer was also injected using the sameprogramme for background subtraction. All data were fitted to a 1:1binding model using Prism9 (GraphPad).

To compare the binding profiles between BA.2 and BA.4/5 RBD for mAbOmi-06/Omi-25/Omi-26, a Protein A sensor chip (Cytiva) was used. mAb inthe IgG form was immobilised onto the sample flow cell of the sensorchip to a similar level (˜350 RU). The reference flow cell was leftblank. A single injection of RBD was performed over the two flow cellsat 200 nM, at a flow rate of 30 μl min-1 Running buffer was alsoinjected using the same programme for background subtraction. Thesensorgrams were plotted using Prism9 (GraphPad).

To compare the binding profiles between BA.2 and BA.4/5 RBD for mAbOmi-02/Omi-23/Omi-31, a Biotin CAPture Kit (Cytiva) was used.Biotinylated BA.2 and BA.4/5 RBD was immobilised onto the sample flowcell of the sensor chip to a similar level (˜120 RU). The reference flowcell was left blank. A single injection of mAb Fab was performed overthe two flow cells at 200 nM, at a flow rate of 30 μl min-1. Runningbuffer was also injected using the same programme for backgroundsubtraction. The sensorgrams were plotted using Prism9 (GraphPad).

To determine the binding kinetics between BA.2.75 or BA.2+R493Q RBD andACE2, a Protein A sensor chip (Cytiva) was used. ACE2-Fc was immobilisedonto the sample flow cell of the sensor chip. The reference flow cellwas left blank. RBD was injected over the two flow cells at a range offive concentrations prepared by serial two-fold dilutions, at a flowrate of 30 μl min-1 using a single-cycle kinetics programme. Runningbuffer was also injected using the same programme for backgroundsubtraction. All data were fitted to a 1:1 binding model using BiacoreT200 Evaluation Software 3.1.

To confirm the binding kinetics between the BA.2.75 RBD and ACE2, aBiotin CAPture Kit (Cytiva) was used. Biotinylated ACE2 (bio-ACE2) wasimmobilised onto the sample flow cell of the sensor chip. The referenceflow cell was left blank. The BA.2.75 RBD was injected over the two flowcells at a range of five concentrations prepared by serial two-folddilutions, at a flow rate of 30 μl min⁻¹ using a single-cycle kineticsprogramme. Running buffer was also injected using the same programme forbackground subtraction. All data were fitted to a 1:1 binding modelusing Biacore T200 Evaluation Software 3.1.

To determine the binding kinetics between the BA.2.75 or BA.2 RBD andmAbs, a Biotin CAPture Kit (Cytiva) was used. Biotinylated RBD wasimmobilised onto the sample flow cell of the sensor chip. The referenceflow cell was left blank. The Fab of Omi-18 or Omi-32 was injected overthe two flow cells at a range of five concentrations prepared by serialtwo-fold dilutions, at a flow rate of 30 μl min⁻¹ using a single-cyclekinetics programme. For the binding of Omi-20 for bio-BA.2 RBD, the Fabof Omi-20 was injected over the two flow cells at a range of fiveconcentrations prepared by serial two-fold dilutions, at a flow rate of30 μl min⁻¹ using a single-cycle kinetics programme. For the binding ofOmi-20 for bio-BA.2.75 RBD, the Fab of Omi-20 was injected over the twoflow cells at a range of eight concentrations prepared by serial twofolddilutions, at a flow rate of 30 μl min⁻¹. Running buffer was alsoinjected using the same programme for background subtraction. All datawere fitted to a 1:1 binding model using Biacore T200 EvaluationSoftware 3.1.

To compare the binding profiles between BA.2 and BA.2.75 RBD for mAbOmi-29, a Biotin CAPture Kit (Cytiva) was used. Biotinylated BA.2 andBA.2.75 RBD was immobilised onto the sample flow cell of the sensor chipto a similar level (˜110 RU). The reference flow cell was left blank. Asingle injection of mAb Fab was performed over the two flow cells at 1μM, at a flow rate of 30 μl min⁻¹. Running buffer was also injectedusing the same programme for background subtraction. The sensorgramswere plotted using Prism9 (GraphPad).

To compare the binding profiles between BA.2 and BA.2.75 RBD for mAbOmi-36, a sensor chip Protein A (Cytiva) was used. mAb Omi-36 in the IgGform was immobilised onto the sample flow cell of the sensor chip. Thereference flow cell was left blank. A single injection of RBD wasperformed over the two flow cells at 200 nM, at a flow rate of 30 μlmin⁻¹. Running buffer was also injected using the same programme forbackground subtraction. The sensorgrams were plotted using Prism9(GraphPad).

IgG mAbs and Fabs Production

AstraZeneca and Regeneron antibodies were provided by AstraZeneca, Vir,Lilly and Adagio antibodies were provided by Adagio, LY-CoV 1404 wasprovided by LifeArc. For the in-house antibodies, heavy and light chainsof the indicated antibodies were transiently transfected into 293Y or293T cells and antibody purified from supernatant on protein A aspreviously described (Nutalai et al., 2022). Fabs were digested frompurified IgGs with papain using a Pierce Fab Preparation Kit (ThermoFisher), following the manufacturer's protocol.

Quantification and Statistical Analysis

Statistical analyses are reported in the results and figure legends.Neutralization was measured by FRNT. The percentage of focus reductionwas calculated and IC₅₀ (FRNT50) was determined using the probit programfrom the SPSS package. The Wilcoxon matched-pairs signed rank test wasused for the analysis and two-tailed P values were calculated ongeometric mean values.

Crystallization

RBD proteins were deglycosylated with Endoglycosidase F 1 before usedfor crystallization. Omicron BA.1-RBD was mixed with Omi-12 and beta-54Fabs, separately, in a 1:1:1 molar ratio, with a final concentration of7 mg ml-1. These complexes were separately incubated at room temperaturefor 30 min. Initial screening of crystals was set up in Crystalquick96-well X plates (Greiner Bio-One) with a Cartesian Robot using thenanoliter sitting-drop vapor-diffusion method, with 100 nL of proteinplus 100 nL of reservoir in each drop, as previously described (Walteret al., 2003, Journal of Applied Crystallography 36, 308-314).

Crystals of BA.1-RBD/Omi-12/beta-54 were formed in Hampton ResearchPEGRx condition 1-46, containing 0.1 M Sodium citrate tribasic dihydratepH 5.0 and 18% (w/v) PEG 20000. Complex of BA.1-RBD/Omi-12/beta-54 wasscreen in Hampton Research Ammonium sulphate screen C2, containing 2.4 M(NH₄)₂SO₄ and 0.1 M citric acid pH 5.0, but only crystals of Fab Omi-12alone were formed in this condition.

Crystallization of BA.2.75 RBD

Purified BA.2.75 RBD was deglycosylated with Endoglycosidase H1 andmixed with ACE2 in a 1:1 molar ratio, with a final concentration of 13.0mg ml⁻¹. Initial screening of crystals was set up in Crystalquick96-well X plates (Greiner Bio-One) with a Cartesian Robot using thenanoliter sitting-drop vapor-diffusion method, with 100 nL of proteinplus 100 nL of reservoir in each drop, as previously described (Walteret al., 2003). Crystals of BA.2.75 RBD-ACE2 complex were formed inHampton Research PEGRx condition 2-25, containing 0.1% (w/v)n-Octyl-b-D-glucoside, 0.1 M Sodium citrate tribasic dihydrate pH 5.5and 22% (w/v) PEG 3350. Diffraction data were collected at 100 K atbeamline I03 of Diamond Light Source, UK, using the automated queuesystem that allows unattended automated data collection(https://www.diamond.ac.uk/Instruments/Mx/I03/I03-Manual/Unattended-Data-Collections.html).

X-Ray Data Collection, Structure Determination and Refinement

Diffraction data were collected at 100 K at beamline I03 of DiamondLight Source, UK. All data were collected as part of an automated queuesystem allowing unattended automated data collection(https://www.diamond.ac.uk/Instruments/Mx/I03/I03-Manual/Unattended-Data-Collections.html).Crystals were pre-frozen by mounting in loops and soaked for a second incryo-protectant containing 25% glycerol and 75% mother liquor.Diffraction images of 0.1° rotation were recorded on an Eiger2 XE 16Mdetector (exposure time from 0.018 s per image, beam size 80×20 μm, 10%beam transmission and wavelength of 0.9762 Å). Data were indexed,integrated and scaled with the automated data processing programXia2-dials (Winter, 2010, Journal of applied crystallography 43,186-190; Winter et al., 2018, Acta Crystallogr D Struct Biol 74, 85-97).360° of data was collected from a single crystal for each of the datasets.

Structures were determined by molecular replacement with PHASER (McCoyet al., 2007, J Appl Crystallogr 40, 658-674). VhVl and ChCl domainswhich have the most sequence similarity to previously determinedSARS-CoV-2 RBD/Fab structures (Dejnirattisai et al., 2021, Cell 184,2183-2200 e2122; Dejnirattisai et al., 2021, Cell 184, 2939-2954 e2939;Huo et al., 2020, Cell Host Microbe 28, 445-454; Liu et al., 2021, Cell184, 4220-4236 e4213; Supasa et al., 2021, Cell 184, 2201-2211 e2207;Zhou et al., 2021, Cell 184, 2348-2361 e2346; Zhou et al., 2020, Naturestructural & molecular biology 27, 950-958) were used as search modelsfor each of the current structure determination.

Model rebuilding with COOT (Emsley et al., 2010, BiologicalCrystallography 66, 486-501) and refinement with Phenix (Liebschner etal., 2019, Acta Crystallogr D Struct Biol 75, 861-877) were used for allthe structures. Due to the lower resolution, only rigid-body and groupB-factor refinement were performed for structures ofBA.1-RBD/0-12/Beta-54 complex.

Data collection and structure refinement statistics are given in Tables19 and 25. Structural comparisons used SHP (Stuart et al., 1979, J MolBiol 134, 109-142), residues forming the RBD/Fab interface wereidentified with PISA (Krissinel and Henrick, 2007, J Mol Biol 372,774-797) and figures were prepared with PyMOL (The PyMOL MolecularGraphics System, Version 1.2r3pre, Schrödinger, LLC).

Example 5 Antibody Structure

The structure of the BA.1 RBD/Fab Omi-12/Fab Beta-54 ternary complex wasdetermined to 5.5 Å resolution (Table 19, FIG. 6A). A slight clash wasobserved between the two Fabs despite the BLI experiment showing nosignificant competition for binding between them. A high-resolutionstructure of un-complexed Omi-12 fab (2.1 Å resolution, Table 19) hasbeen modelled into the electron density for the complex (FIGS. 6B, 6C).Superimposing Fab 253 onto Fab Omi-12 suggests that Q493R would clashwith the H2 loop of Fab 253, whereas in Omi-12, H2 adopts a slightlyflattened structure. This structural change is attributable to antibodymaturation via the somatic mutation V53P in the heavy chain variableregion of Omi-12 which forms a stacking interaction with Y489 (FIG. 6D).

Omi-12 and Antibody 253 are both derived from the germline heavy chainIGHV1-58. Interestingly, similar to antibody 253, other antibodiesderived from the germline heavy chain IGHV1-58 described herein, i.e.Beta-47, Beta-25, antibody 55, antibody 165 and antibody 318, also has avaline (V) at position 53 in the heavy chain variable region, i.e.valine (V) at position 53 in SEQ ID NO: 262 (antibody 253), SEQ ID NO:591 (Beta-47), SEQ ID NO: 461 (Beta-25), SEQ ID NO: 62 (antibody 55),SEQ ID NO: 182 (antibody 165) and SEQ ID NO: 332 (antibody 318).Position 53 in these sequences corresponds to position 58 according toIMGT numbering. Based on the data, modification of any of theseantibodies by substitution of valine at position 53 with proline (i.e.V53P absolute numbering, or V58P according to IMGT numbering) wouldresult in an antibody that would be effective against Omicron.

Furthermore, antibody AZD8895 (heavy chain variable region amino acidsequences provided in SEQ ID NO: 963 and light chain variable regionamino acid sequence provided in SEQ ID NO: 965) is also derived from thegermline heavy chain IGHV1-58 (e.g. see Dong et al. Nat Microbiol 6,1233-1244 (2021)). AZD8895 has an isoleucine (I) at position 53 in theheavy chain variable region, which corresponds to position 58 accordingto IMGT numbering. Based on the data herein, modification of the heavychain variable region AZD8895 (SEQ ID NO: 963) by substitution ofisoleucine at position 53 with proline (i.e. I53P) using absolutenumbering, or 158P using IMGT numbering, would result in an antibodythat would be effective against Omicron.

Hence, the data indicate that the modification of VH1-58 antibodies suchthat a proline is present at position 53 (corresponding to position 58according to IMGT numbering) in the heavy chain variable region wouldmake them particularly effective against Omicron.

ACE2/BA.2.75 RBD Structure

To elucidate the molecular mechanism for high affinity, the structure ofthe BA.2.75 RBD with ACE2 was determined by crystallography (accordingto the methods described in Example 4). As expected the binding mode wasessentially indistinguishable from that observed before (FIG. 20A),although there were significant rearrangements outside of the ACE2footprint, with the flexible RBD 371-375 loop re-arranging and part ofthe C-terminal 6×His tag becoming ordered. FIG. 20B shows a close-up ofthe binding interface, compared with the ACE2/BA.2 RBD complex. In othercomplexes (with either R or Q at RBD 493) K31 of ACE2 tends to bedisordered, whereas it is well ordered in the BA.2.75 complex, allowingK31 to form a potential hydrogen bond with the glutamine sidechainpossibly increasing the affinity of ACE2.

Tables

TABLE 1 SEQ ID NOs of antibodies raised against early pandemic strainsHeavy Light Chain Heavy Chain Light Antibody protein Chain sequenceChain number sequence nucleotide protein nucleotid CDRH1 CDRH2 CDRH3CDRL1 CDRL2 CDRL3  2 2 1 4 3 5 6 7 8 9 10  22 12 11 14 13 15 16 17 18 1920  40 22 21 24 23 25 26 27 28 29 30  44 32 31 34 33 35 36 37 38 39 40 45 42 41 44 43 45 46 47 48 49 50  54 52 51 54 53 55 56 57 58 8 60  5562 61 64 63 65 66 67 68 69 70  58 72 71 74 73 75 76 77 78 79 80  61 8281 84 83 85 86 87 88 89 90  75 92 91 94 93 95 96 97 98 99 100  88 102101 104 103 105 106 107 108 109 110 111 112 111 14 113 115 116 117 118119 120 132 122 121 124 123 125 126 127 128 129 130 140 132 131 134 133135 136 137 138 139 140 148 142 141 144 143 145 146 147 148 149 150 150152 151 154 153 155 156 157 158 159 160 158 162 161 164 163 165 166 167168 169 170 159 172 171 174 173 175 176 177 178 179 180 165 182 181 184183 185 186 187 188 189 190 170 192 191 194 193 195 196 197 198 199 200175 202 201 204 203 205 206 207 208 209 210 177 212 211 214 213 215 216217 218 219 220 181 222 221 224 223 225 226 227 228 229 230 182 232 231234 233 235 236 237 238 239 240 183 242 241 244 243 245 246 247 248 249250 222 252 251 254 253 255 256 257 258 259 260 253 262 261 264 263 265266 267 268 269 270 253H55L 262 261 64 63 265 266 267 68 69 70 253H165I262 261 184 183 265 266 267 188 189 190 269 272 271 274 273 275 276 277278 279 280 278 282 281 284 283 285 286 287 288 289 290 281 292 291 294293 295 296 297 298 299 300 282 302 301 304 303 305 306 307 308 309 310285 312 311 314 313 315 316 317 318 319 320 316 322 321 324 323 325 326327 328 329 330 318 332 331 334 333 335 336 337 338 339 340 334 342 341344 343 345 346 347 348 349 350 361 352 351 354 353 355 356 357 358 359360 382 362 361 364 363 365 366 367 368 369 370 384 372 371 374 373 375376 377 378 379 380 394 382 381 384 383 385 386 387 388 389 390 398 392391 394 393 395 396 397 398 399 400

TABLE 2 SEQ ID NOs of antibodies raised against the Beta strain HeavyHeavy Light Light Chain Chain Chain Chain Antibody nucleotide proteinnucleotide protein number sequence sequence sequence sequence CDRH1CDRH2 CDRH3 CDRL1 CDRL2 CDRL3 Beta-06 401 402 403 404 405 406 407 408409 410 Beta-10 411 412 413 414 415 416 417 418 419 420 Beta-20 421 422423 424 425 426 427 428 429 430 Beta-22 431 432 433 434 435 436 437 438439 440 Beta-23 441 442 443 444 445 446 447 448 449 450 Beta-24 451 452453 454 455 456 457 458 459 460 Beta-25 461 462 463 464 465 466 467 468469 470 Beta-26 471 472 473 474 475 476 477 478 479 480 Beta-27 481 482483 484 485 486 487 488 489 490 Beta-29 491 492 493 494 495 496 497 498499 500 Beta-30 501 502 503 504 505 506 507 508 509 510 Beta-32 511 512513 514 515 516 517 518 519 520 Beta-33 521 522 523 524 525 526 527 528529 530 Beta-34 531 532 533 534 535 536 537 538 539 540 Beta-38 541 542543 544 545 546 547 548 549 550 Beta-40 551 552 553 554 555 556 557 558559 560 Beta-43 561 562 563 564 565 566 567 568 569 570 Beta-44 571 572573 574 575 576 577 578 579 580 Beta-45 581 582 583 584 585 586 587 588589 590 Beta-47 591 592 593 594 595 596 597 598 599 600 Beta-48 601 602603 604 605 606 607 608 609 610 Beta-49 611 612 613 614 615 616 617 618619 620 Beta-50 621 622 623 624 625 626 627 628 629 630 Beta-51 631 632633 634 635 636 637 638 639 640 Beta-53 641 642 643 644 645 646 647 648649 650 Beta-54 651 652 653 654 655 656 657 658 659 660 Beta-55 661 662663 664 665 666 667 668 669 670 Beta-56 671 672 673 674 675 676 677 678679 680

TABLE 3 SEQ ID NOs of antibodies raised against the Omicron strain HeavyHeavy Chain Light Light Chain Antibody Chain protein Chain proteinnumber nucleotide sequence nucleotide sequence CDRH1 CDRH2 CDRH3 CDRL1CDRL2 CDRL3 Omi02 681 682 683 684 685 686 687 688 689 690 Omi03 691 692693 694 695 696 697 698 699 700 Omi06 701 702 703 704 705 706 707 708709 710 Omi08 711 712 713 714 715 716 717 718 719 720 Omi09 721 722 723724 725 726 727 728 729 730 Omi12 731 732 733 734 735 736 737 738 739740 Omi16 741 742 743 744 745 746 747 748 749 750 Omi17 751 752 753 754755 756 757 758 759 760 Omi18 761 762 763 764 765 766 767 768 769 770Omi20 771 772 773 774 775 776 777 778 779 780 Omi23 781 782 783 784 785786 787 788 789 790 Omi24 791 792 793 794 795 796 797 798 799 800 Omi25801 802 803 804 805 806 807 808 809 810 Omi26 811 812 813 814 815 816817 818 819 820 Omi27 821 822 823 824 825 826 827 828 829 830 Omi28 831832 833 834 835 836 837 838 839 840 Omi29 841 842 843 844 845 846 847848 849 850 Omi30 851 852 853 854 855 856 857 858 859 860 Omi31 861 862863 864 865 866 867 868 869 870 Omi32 871 872 873 874 875 876 877 878879 880 Omi33 881 882 883 884 885 886 887 888 889 890 Omi34 891 892 893894 895 896 897 898 899 900 Omi35 901 902 903 904 905 906 907 908 909910 Omi36 911 912 913 914 915 916 917 918 919 920 Omi38 921 922 923 924925 926 927 928 929 930 Omi39 931 932 933 934 935 936 937 938 939 940Omi41 941 942 943 944 945 946 947 948 949 950 Omi42 951 952 953 954 955956 957 958 959 960

TABLE 4 Examples of the mixed chain antibodies generated from antibodiesderived from the same germline heavy chain IGHV3-53 Heavy chain(H)/light chain (L) of antibody Omi03H Omi18H Omi29H Beta-27H 150H 158H175H 222H 269H Omi03L — Omi18H Omi29H Beta-27H 150H 158H 175H 222H 269HOmi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi18L Omi03H —Omi29H Beta-27H 150H 158H 175H 222H 269H Omi18L Omi18L Omi18L Omi18LOmi18L Omi18L Omi18L Omi18L Omi29L Omi03H Omi18H — Beta-27H 150H 158H175H 222H 269H Omi29L Omi29L Omi29L Omi29L Omi29L Omi29L Omi29L Omi29LBeta-27L Omi03 Omi18 Omi29 — 150H 158H 175H 222H 269H HBeta- HBeta-HBeta- Beta- Beta- Beta- Beta- Beta- 27L 27L 27L 27L 27L 27L 27L 27L150L Omi03 Omi18 Omi29 Beta-27H — 158H 175H 222H 269H H150L H150L H150L150L 150L 150L 150L 150L 158L Omi03 Omi18 Omi29 Beta-27H 150H — 175H222H 269H H158L H158L H158L 158L 158L 158L 158L 158L 175L Omi03 Omi18Omi29 Beta-27H 150H 158H — 222H 269H H175L H175L H175L 175L 175L 175L175L 175L 222L Omi03 Omi18 Omi29 Beta-27H 150H 158H 175H — 269H H222LH222L H222L 222L 222L 222L 222L 222L 269L Omi03 Omi18 Omi29 Beta-27H150H 158H 175H 222H — H269L H269L H269L 269L 269L 269L 269L 269L

TABLE 5 Examples of the mixed chain antibodies generated from antibodiesderived from the same germline heavy chain IGHV3-53 + IGHV3-66 Heavychain (H)/light chain (L) of antibody Omi03H Omi18H Omi29H Omi16H Omi17HOmi20H Omi27H Omi28H Omi36H Beta-27H 150H 158H 175H 222H 269H 40H 398HOmi03L — Omi18H Omi29H Omi16H Omi17H Omi20H Omi27H Omi28H Omi36HBeta-27H 150H 158H 175H 222H 269H 40H 398H Omi03L Omi03L Omi03L Omi03LOmi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi03L Omi03LOmi03L Omi03L Omi18L Omi03H — Omi29H Omi16H Omi17H Omi20H Omi27H Omi28HOmi36H Beta-27H 150H 158H 175H 222H 269H 40H 398H Omi18L Omi18L Omi18LOmi18L Omi18L Omi18L Omi18L Omi18L Omi18L Omi18L Omi18L Omi18L Omi18LOmi18L Omi18L Omi18L Omi29L Omi03H Omi18H — Omi16H Omi17H Omi20H Omi27HOmi28H Omi36H Beta-27H 150H 158H 175H 222H 269H 40H 398H Omi29L Omi29LOmi29L Omi29L Omi29L Omi29L Omi29L Omi29L Omi29L Omi29L Omi29L Omi29LOmi29L Omi29L Omi29L Omi29L Omi16H Omi03H Omi18H Omi29H — Omi17H Omi20HOmi27H Omi28H Omi36H Beta-27H 150H 158H 175H 222H 269H 40H 398H Omi16LOmi16L Omi16L Omi 16L Omi16L Omi16L Omi16L Omi16L Omi16L Omi16L Omi16LOmi16L Omi16L Omi16L Omi16L Omi16L Omi17H Omi03H Omi18H Omi29H Omi16H —Omi20H Omi27H Omi28H Omi36H Beta-27H 150H 158H 175H 222H 269H 40H 398HOmi17L Omi17L Omi17L Omi17L Omi17L Omi17L Omi17L Omi17L Omi17L Omi17LOmi17L Omi17L Omi17L Omi17L Omi17L Omi17L Omi20H Omi03H Omi18H Omi29HOmi16H Omi17H — Omi27H Omi28H Omi36H Beta-27H 150H 158H 175H 222H 269H40H 398H Omi20L Omi20L Omi20L Omi20L Omi20L Omi20L Omi20L Omi20L Omi20LOmi20L Omi20L Omi20L Omi20L Omi20L Omi20L Omi20L Omi27H Omi03H Omi18HOmi29H Omi16H Omi17H Omi20H — Omi28H Omi36H Beta-27H 150H 158H 175H 222H269H 40H 398H Omi27L Omi27L Omi27L Omi27L Omi27L Omi27L Omi27L Omi27LOmi27L Omi27L Omi27L Omi27L Omi27L Omi27L Omi27L Omi27L Omi28H Omi03HOmi18H Omi29H Omi16H Omi17H Omi20H Omi27H — Omi36H Beta-27H 150H 158H175H 222H 269H 40H 398H Omi28L Omi28L Omi28L Omi28L Omi28L Omi28L Omi28LOmi28L Omi28L Omi28L Omi28L Omi28L Omi28L Omi28L Omi28L Omi28L Omi36HOmi03H Omi18H Omi29H Omi16H Omi17H Omi20H Omi27H Omi28H — Beta-27H 150H158H 175H 222H 269H 40H 398H Omi36L Omi36L Omi36L Omi36L Omi36L Omi36LOmi36L Omi36L Omi36L Omi36L Omi36L Omi36L Omi36L Omi36L Omi36L Omi36LBeta-27L Omi03H Omi18H Omi29H Omi16H Omi17H Omi20H Omi27H Omi28H Omi36H— 150H 158H 175H 222H 269H 40H 398H Beta-27L Beta-27L Beta-27L Beta-27LBeta-27L Beta-27L Beta-27L Beta-27L Beta-27L Beta-27L Beta-27L Beta-27LBeta-27L Beta-27L Beta- 27L Beta-27L 150L Omi03 Omi18 Omi29 Omi16 Omi17Omi20 Omi27 Omi28 Omi36 Beta-27H — 158H 175H 222H 269H 40H 150L 398HH150L H150L H150L H150L H150L H150L H150L H150L H150L 150L 150L 150L150L 150L 150L 158L Omi03 Omi18 Omi29 Omi16 Omi17 Omi20 Omi27 Omi28Omi36 Beta-27H 150H — 175H 222H 269H 40H 158L 398H H158L H158L H158LH158L H158L H158L H158L H158L H158L 158L 158L 158L 158L 158L 158L 175LOmi03 Omi18 Omi29 Omi16 Omi17 Omi20 Omi27 Omi28 Omi36 Beta-27H 150H 158H— 222H 269H 40H 175L 398H H175L H175L H175L H175L H175L H175L H175LH175L H175L 175L 175L 175L 175L 175L 175L 222L Omi03 Omi18 Omi29 Omi16Omi17 Omi20 Omi27 Omi28 Omi36 Beta-27H 150H 158H 175H — 269H 40H 222L398H H222L H222L H222L H222L H222L H222L H222L H222L H222L 222L 222L222L 222L 222L 222L 269L Omi03 Omi18 Omi29 Omi16 Omi17 Omi20 Omi27 Omi28Omi36 Beta-27H 150H 158H 175H 222H — 40H 269L 398H H269L H269L H269LH269L H269L H269L H269L H269L H269L 269L 269L 269L 269L 269L 269L 40LOmi03 Omi18 Omi29 Omi16 Omi17 Omi20 Omi27 Omi28 Omi36 Beta-27H 150H 40L158H 175H 222H 269H — 398H H40L H40L H40L H40L H40L H40L H40L H40L H40L40L 40L 40L 40L 40L 40L 398L Omi03 Omi18 Omi29 Omi16 Omi17 Omi20 Omi27Omi28 Omi36 Beta-27H 150H 158H 175H 222H 269H 40H 398L — H398L H398LH398L H398L H398L H398L H398L H398L H398L 398L 398L 398L 398L 398L 398L

TABLE 6 Examples of the mixed chain antibodies generated from antibodiesderived from the same germline heavy chain IGHV1-58 Heavy chain(H)/light chain (L) of antibody Omi12H Beta-47H Beta-25H 55H 165H 253H318H Omi12L — Beta-47H Beta-25H 55H Omi12L 165H 253H 318H Omi12L Omi12LOmi12L Omi12L Omi12L Beta-47L Omi12H — Beta 55H 165H 253H 318H Beta- 25HBeta- Beta- Beta- Beta- 47L Beta-47L 47L 47L 47L 47L Beta-25L Omi12HBeta- — 55H Beta 165H Beta 253H Beta 318H Beta Beta- 47H 25L 25L 25L 25L25L Beta-25L 55L Omi12H 55L Beta-47H Beta-25H — 165H 55L 253H 55L 318H55L 55L 55L 165L Omi12 Beta-47H Beta-25H 55H 165L — 253H 165L 318H 165LH165L 165L 165L 253L Omi12 Beta-47H Beta-25H 55H 253L 165H 253L — 318H253L H253L 253L 253L 318L Omi12 Beta-47H Beta-25H 55H 318L 165H 318L253H 318L — H318L 318L 318L

TABLE 7 Examples of the mixed chain antibodies generated from antibodiesderived from the same germline heavy chain IGHV1-69 Heavy chain (H)/light chain (L) of antibody Beta-49H Beta-50H Omi02H Omi24H Omi30HOmi31H Omi34H Omi38H Beta-49L — Beta- Omi02H Omi24H Omi30H Omi31H Omi34HOmi38H 50H Beta- Beta- Beta- Beta- Beta- Beta- Beta-49L 49L 49L 49L 49L49L 49L Beta-50L Beta- — Omi02H Omi24H Omi30H Omi31H Omi34H Omi38H 49HBeta- Beta- Beta- Beta- Beta- Beta- Beta-50L 50L 50L 50L 50L 50L 50LOmi02L Beta-49H Beta-50H — Omi24H Omi30H Omi31H Omi34H Omi38H Omi02LOmi02L Omi02L Omi02L Omi02L Omi02L Omi02L Omi24L Beta-49H Beta-50HOmi02H — Omi30H Omi31H Omi34H Omi38H Omi24L Omi24L Omi24L Omi24L Omi24LOmi24L Omi24L Omi30L Beta-49H Beta-50H Omi02H Omi24H — Omi31H Omi34HOmi38H Omi30L Omi30L Omi30L Omi30L Omi30L Omi30L Omi30L Omi31L Beta-49HBeta-50H Omi02H Omi24H Omi30H — Omi34H Omi38H Omi31L Omi31L Omi31LOmi31L Omi31L Omi31L Omi31L Omi34H Beta-49H Beta-50H Omi02H Omi24HOmi30H Omi31H — Omi38H Omi34L Omi34L Omi34L Omi34L Omi34L Omi34L Omi34LOmi38H Beta-49H Beta-50H Omi02H Omi24H Omi30H Omi31H Omi34H — Omi38LOmi38L Omi38L Omi38L Omi38L Omi38L Omi38L

TABLE 8 Examples of the mixed chain antibodies generated from antibodiesderived from the same germline heavy chain IGHV3-30 Heavy chain(H)/light chain (L) of antibody Beta-22H Beta-29H 159H Omi09H Beta-22L —Beta- 159H Omi09H 29H Beta- 22L Beta- Beta-22L 22L Beta-29L Beta-22H —159H Omi09H Beta 29L Beta- 29L Beta 29L 159L Beta-22H Beta-29H — Omi09159L 159L H159L Omi09L Beta-22H Beta-29H 159H — Omi09L Omi09L Omi09L

TABLE 9 Examples of the mixed chain antibodies generated from antibodiesderived from the same germline heavy chain IGHV3-33 Heavy chain(H)/light chain (L) of antibody Beta-20H Beta-43H Omi32H Omi33H Beta-20L— Beta- Omi32H Omi33H 43H Beta- 20L Beta- 20L Beta-20L Beta-43L Beta- —Omi32H Omi33H 20H Beta- 43L Beta- 43L Beta-43L Omi32L Beta-20H Beta-43H— Omi33H Omi32L Omi32L Omi32L Omi33L Beta-20H Beta-43H Omi32H — Omi33LOmi33L Omi33L

TABLE 10 Examples of the mixed chain antibodies generated fromantibodies derived from the same germline heavy chain IGHV 1-18 Heavychain (H)/lightchain (L) of antibody 278H Beta-44H Omi26H Omi41H 278L —Beta-44H Omi26 Omi41 278L H278L H278L Beta-44L 278H — Omi26H Omi41HBeta- 44L Beta- Beta- 44L 44L Omi26L 278H Beta-44H — Omi41H Omi26LOmi26L Omi26L Omi41L 278H Beta-44H Omi26H — Omi41L Omi41L Omi41L

TABLE 11 Examples of the mixed chain antibodies generated fromantibodies derived from the same germline heavy chain IGHV3-9 Heavychain (H)/light chain (L) of antibody 58H Omi25H Omi35H Omi42H 58L —Omi25 Omi35 Omi42 H58L H58L H58L Omi25L 58H — Omi35H Omi42H Omi25LOmi25L Omi25L Omi35L 58H Omi25H — Omi42H Omi35L Omi35L Omi35L Omi42L 58HOmi25H Omi35H — Omi42L Omi42L Omi42L

TABLE 12 Examples of the mixed chain antibodies generated fromantibodies derived from the same germline heavy chain IGHV4-31 Heavychain (H)/light chain (L) of antibody Beta-56H Omi23H Beta-56L — Omi23HBeta-56L Omi23L Beta-56HOmi23L —

TABLE 13 IC50 titres of 22 Omicron SARS-CoV-2-specific human mAbsagainst live virus strains Victoria, Alpha, Beta, Gamma, Delta andOmicron (BA.1). Authentic virus - IC50 (μg/ml) Omicron Victoria AlphaBeta Gamma Delta (BA.1) Omi-02 0.015 ± 0.014 ± 0.009 ± 0.004 ± 0.014 ±0.013 ± 0.001 0.005 0.000 0.000 0.003 0.001 Omi-03 0.007 ± 0.012 ± 0.009± 0.004 ± 0.004 ± 0.009 ± 0.000 0.007 0.001 0.000 0.000 0.002 Omi-060.007 ± 0.011 ± 0.012 ± 0.010 ± 5.040 ± 0.054 ± 0.001 0.002 0.000 0.0030.747 0.005 Omi-08 0.014 ± 0.022 ± 0.007 ± 0.024 ± 0.048 ± 0.008 ± 0.0070.002 0.000 0.007 0.012 0.004 Omi-09 0.004 ± 0.002 ± 1.218 ± 2.373 ±0.008 ± 0.011 ± 0.001 0.000 0.324 1.008 0.002 0.005 Omi-12 0.005 ± 0.003± 0.006 ± 0.003 ± 0.003 ± 0.004 ± 0.000 0.001 0.001 0.000 0.000 0.001Omi-16 0.016 ± 0.022 ± 0.018 ± 0.022 ± 0.016 ± 0.019 ± 0.002 0.009 0.0040.007 0.002 0.003 Omi-17 0.066 ± 0.098 ± 0.021 ± 0.021 ± 0.074 ± 0.028 ±0.015 0.027 0.007 0.007 0.019 0.005 Omi-18 0.041 ± 0.038 ± 0.018 ± 0.016± 0.025 ± 0.006 ± 0.005 0.008 0.006 0.004 0.000 0.003 Omi-20 0.012 ±0.023 ± 0.019 ± 0.019 ± 0.008 ± 0.043 ± 0.002 0.004 0.009 0.006 0.0010.012 Omi-23 0.005 ± 0.009 ± 0.020 ± 0.018 ± 0.006 ± 0.044 ± 0.002 0.0040.005 0.006 0.002 0.013 Omi-24 0.005 ± 0.008 ± 0.006 ± 0.010 ± >10 0.007± 0.001 0.003 0.001 0.005 0.001 Omi-25 0.003 ± 0.007 ± 0.059 ± 0.257 ±0.006 ± 0.046 ± 0.001 0.001 0.007 0.079 0.002 0.015 Omi-26 0.005 ± 0.010± 0.055 ± 0.214 ± 0.005 ± 0.034 ± 0.000 0.003 0.020 0.046 0.001 0.000Omi-27 0.026 ± 0.032 ± 0.019 ± 0.017 ± 0.010 ± 0.091 ± 0.001 0.012 0.0060.006 0.001 0.050 Omi-28 0.028 ± 0.028 ± 0.019 ± 0.033 ± 0.018 ± 0.032 ±0.004 0.001 0.010 0.008 0.002 0.009 Omi-29 0.044 ± 0.066 ± 0.048 ± 0.040± 0.029 ± 0.036 ± 0.002 0.034 0.020 0.007 0.004 0.003 Omi-30 0.109 ±0.043 ± 0.028 ± 0.038 ± >10 0.058 ± 0.035 0.016 0.009 0.004 0.008 Omi-310.007 ± 0.020 ± 0.011 ± 0.017 ± >10 0.010 ± 0.001 0.003 0.005 0.0060.002 Omi-32 0.032 ± 0.102 ± 0.460 ± 0.430 ± 0.012 ± 0.024 ± 0.016 0.0410.092 0.012 0.002 0.011 Omi-33 0.028 ± 0.057 ± 0.136 ± 0.132 ± 0.011 ±0.026 ± 0.005 0.017 0.002 0.037 0.001 0.008 Omi-34 0.003 ± 0.041 ± 0.003± 0.008 ± >10 0.028 ± 0.001 0.027 0.000 0.002 0.009 Omi-35 0.057 ± 0.080± 0.128 ± 0.136 ± 0.280 ± 0.069 ± 0.003 0.030 0.058 0.024 0.059 0.032Omi-36 0.056 ± 0.047 ± 0.018 ± 0.015 ± 0.026 ± 0.038 ± 0.008 0.009 0.0010.000 0.003 0.006 Omi-38 0.001 ± 0.009 ± 0.004 ± 0.002 ± 0.004 ± 0.054 ±0.000 0.001 0.000 0.000 0.001 0.028 Omi-39 0.015 ± 0.039 ± 0.009 ± 0.014± 0.012 ± 0.025 ± 0.006 0.007 0.000 0.001 0.007 0.004 Omi-41 0.090 ±2.262 ± >10 0.126 ± >10 0.081 ± 0.013 1.199 0.059 0.004 Omi-42 0.016 ±0.024 ± 0.011 ± 0.013 ± 0.019 ± 0.014 ± 0.003 0.001 0.004 0.003 0.0010.002

TABLE 14 IC50 titres of 22 Omicron SARS-COV-2-specific human mAbsagainst pseudovirus strains Victoria, Omicron BA.1, Omicron BA.1.1,Omicron BA.2 and Omicron BA.3. Pseudovirus - IC50 (μg/ml) VictoriaOmicronBA.1 OmicronBA.1.1 OmicronBA.2 OmicronBA.3 Omi-02 0.002 ± 0.0010.004 ± 0.001 0.004 ± 0.001 0.003 ± 0.001 0.019 ± 0.007 Omi-03 0.003 ±0.000 0.005 ± 0.002 0.003 ± 0.001 0.008 ± 0.001 0.022 ± 0.003 Omi-060.007 ± 0.000 0.017 ± 0.003 0.139 ± 0.033 0.039 ± 0.008 0.696 ± 0.106Omi-08 0.008 ± 0.004 0.003 ± 0.000 0.002 ± 0.000 0.114 ± 0.045 0.032 ±0.001 Omi-09 0.006 ± 0.002 0.005 ± 0.000 0.005 ± 0.002 0.008 ± 0.0020.017 ± 0.002 Omi-12 0.006 ± 0.002 0.002 ± 0.000 0.002 ± 0.001 0.003 ±0.001 0.006 ± 0.001 Omi-16 0.014 ± 0.003 0.012 ± 0.002 0.011 ± 0.0030.034 ± 0.012 0.111 ± 0.008 Omi-17 0.023 ± 0.011 0.018 ± 0.012 0.022 ±0.009 0.060 ± 0.004 0.123 ± 0.002 Omi-18 0.008 ± 0.003 0.002 ± 0.0000.002 ± 0.000 0.005 ± 0.000 0.006 ± 0.002 Omi-20 0.009 ± 0.002 0.006 ±0.001 0.005 ± 0.001 0.015 ± 0.003 0.020 ± 0.004 Omi-23 0.005 ± 0.0020.029 ± 0.006 0.023 ± 0.12  0.019 ± 0.005 0.011 ± 0.000 Omi-24 0.005 ±0.000 0.006 ± 0.002 0.054 ± 0.015 0.007 ± 0.001 0.009 ± 0.002 Omi-250.005 ± 0.001 0.023 ± 0.005 0.027 ± 0.005 0.024 ± 0.004 0.050 ± 0.004Omi-26 0.002 ± 0.001 0.006 ± 0.002 0.005 ± 0.001 0.013 ± 0.001 0.018 ±0.002 Omi-27 0.008 ± 0.003 0.026 ± 0.006 0.034 ± 0.009 0.034 ± 0.0050.026 ± 0.007 Omi-28 0.022 ± 0.000 0.011 ± 0.004 0.009 ± 0.002 0.008 ±0.000 0.019 ± 0.000 Omi-29 0.014 ± 0.006 0.017 ± 0.003 0.016 ± 0.0090.056 ± 0.014 0.064 ± 0.017 Omi-30 0.012 ± 0.002 0.008 ± 0.003 0.008 ±0.004 0.011 ± 0.002 0.015 ± 0.003 Omi-31 0.376 ± 0.090 0.029 ± 0.0020.031 ± 0.012 0.013 ± 0.002 0.013 ± 0.004 Omi-32 0.010 ± 0.006 0.017 ±0.000 >10 2.682 ± 0.553 1.018 ± 0.139 Omi-33 0.027 ± 0.011 0.014 ± 0.0050.042 ± 0.018 0.068 ± 0.022 0.133 ± 0.021 Omi-34 0.007 ± 0.004 0.008 ±0.001 0.062 ± 0.004 0.009 ± 0.003 0.014 ± 0.000 Omi-35 0.018 ± 0.0040.058 ± 0.009 0.381 ± 0.086 0.093 ± 0.005 0.044 ± 0.018 Omi-36 0.022 ±0.004 0.009 ± 0.003 0.009 ± 0.003 0.030 ± 0.014 0.178 ± 0.048 Omi-380.015 ± 0.004 0.024 ± 0.015 >10 0.005 ± 0.000 0.008 ± 0.002 Omi-39 0.014± 0.002 0.009 ± 0.004 >10 0.026 ± 0.011 0.014 ± 0.001 Omi-41 >10 0.053 ±0.028 0.037 ± 0.002 >10 0.032 ± 0.007 Omi-42 0.013 ± 0.004 0.007 ± 0.0040.006 ± 0.002 0.021 ± 0.011 0.025 ± 0.012

TABLE 15 IC50 titres of early pandemic SARS-COV-2-specific human mAbsand Beta SARS- CoV-2 specific human mAbs against pseudovirus strainsVictoria, Omicron BA.1, Omicron BA.1.1 and Omicron BA.2. Early IC50(ug/ml) mAbs Omicron Omicron pandemic Victoria Omicron BA.1 BA.1.1 BA.240 0.006 ± 0.002 1.705 ± 0.840 0.544 ± 0.007 0.100 ± 0.007 55 0.006 ±0.002 >10 >10 >10 58 0.019 ± 0.004 0.060 ± 0.041 0.876 ± 0.135 0.043 ±0.007 88 0.005 ± 0.002 >10 >10 >10 132 0.012 ± 0.004 >10 >10 >10 1500.008 ± 0.004 >10 3.500 ± 0.712 >10 158 0.021 ± 0.006 >10 2.843 ± 0.7334.249 ± 0.694 159 >10 >10 >10 >10 165 0.007 ± 0.005 >10 >10 >10 1700.006 ± 0.001 >10 >10 >10 175 0.012 ± 0.004 >10 >10 >10 222 0.006 ±0.000 0.021 ± 0.002 0.023 ± 0.001 0.249 ± 0.082 253 0.021 ± 0.009 0.875± 0.373 0.415+ 0.161 1.100 ± 0.049 269 0.008 ± 0.004 >10 >10 >10 2780.001 ± 0.000 >10 >10 0.326 ± 0.011 281 0.001 ± 0.000 >10 >10 >10 3160.001 ± 0.000 >10 >10 >10 318 0.012 ± 0.003 9.490 ± 4.540 >10 0.303 ±0.190 384 0.001 ± 0.000 >10 >10 >10 398 0.072 ± 0.065 >10 >10 >10 253 +55  0.001 ± 0.000 0.638 ± 0.315 0.451 ± 0.014 >10 253 + 165 0.001 ±0.000 >10 6.591 ± 0.799 >10 IC50 (ug/ml) Omicron Omicron Beta mAbs BetaOmicron BA.1 BA.1.1 BA.2 β06 0.005 ± 0.001 >10 >10 >10 β10 0.021 ±0.008 >10 >10 >10 β20 0.006 ± 0.002 5.679 ± 0.452 1.836 ± 0.780 >10 β220.041 ± 0.014 0.479 ± 0.029 0.130 ± 0.005 >10 β23 0.005 ±0.001 >10 >10 >10 β24 0.002 ± 0.000 >10 >10 >10 β26 0.004 ±0.001 >10 >10 >10 β27 0.003 ± 0.001 0.766 ± 0.043 0.274 ± 0.095 0.348 ±0.030 β29 0.009 ± 0.000 0.095 ± 0.029 0.066 ± 0.002 4.029 ± 0.402 β300.002 ± 0.000 >10 >10 >10 β32 0.023 ± 0.001 >10 >10 >10 β33 0.020 ±0.002 >10 >10 >10 β34 0.030 ± 0.004 >10 >10 >10 β38 0.004 ±0.001 >10 >10 >10 β40 0.001 ± 0.000 0.005 ± 0.001 0.002 ± 0.000 0.008 ±0.002 β43 0.014 ± 0.003 >10 >10 >10 β44 0.008 ± 0.001 >10 >10 >10 β450.010 ± 0.001 >10 >10 >10 β47 0.002 ± 0.000 0.018 ± 0.009 0.011 ± 0.0020.044 ± 0.006 β48 0.003 ± 0.001 5.706 ± 0.676 0.752 ± 0.052 5.042 ±0.650 β49 0.014 ± 0.004 >10 >10 >10 β50 0.008 ± 0.001 >10 >10 >10 β510.003 ± 0.000 >10 >10 >10 β53 0.007 ± 0.001 0.141 ± 0.026 5.849 ± 0.0360.170 ± 0.073 β54 0.002 ± 0.000 0.003 ± 0.001 0.001 ± 0.000 0.076 ±0.029 β55 0.009 ± 0.002 0.033 ± 0.008 0.009 ± 0.001 0.069 ± 0.008

TABLE 16 IC50 titres of commercial mAbs against pseudovirus strainsVictoria, Omicron BA.1, Omicron BA.1.1, Omicron BA.2 and Omicron BA.3.IC50 (ug/ml) Omicron Omicron Omicron Omicron Commercial mAbs VictoriaBA.1 BA.1.1 BA.2 BA.3 Known Antibody 0.002 ± 0.001 >10 >10 0.616 ±0.347 >10 A (REGN 10987) Known Antibody 0.001 ± 0.002 >10 >10 >10 >10 B(REGN 10933) Known Antibody 0.002 ± 0.001 0.308 ± 0.058 >10 0.008 ±0.003 0.019 C (AZD1061) Known Antibody 0.001 ± 0.000 0.246 ± 0.027 0.100± 0.053 1.333 ± 0.317 >10 D (AZD8895) Known Antibody 0.001 ± 0.000 0.232± 0.113 0.806 ± 0.093 0.008 ± 0.001 0.065 ± 0.011 E (AZD7442) KnownAntibody 0.007 ± 0.002 >10 >10 >10 >10 F (ADG10) Known Antibody 0.003 ±0.002 0.348 ± 0.169 0.253 ± 0.070 >10 >10 G (ADG20) Known Antibody 0.014± 0.006 >10 >10 >10 >10 H (ADG30) Known Antibody 0.002 ±0.000 >10 >10 >10 >10 I (Ly-CoV-555) Known Antibody 0.014 ±0.010 >10 >10 >10 >10 J (Ly-CoV16) Known Antibody 0.587 ± 0.286 0.094 ±0.008 0.138 ± 0.020 0.638 ± 0.107 0.228 ± 0.009 K (S309)

TABLE 17 Properties of omicron antibodies Heavy Chain #Amino acid mAbsV-GENE J-GENE D-GENE substitutions Omi-02 1-69*01 , or 2*01 2-21*02 71-69D*01 Omi-03 3-53*01 4*02 1-26*01 5 Omi-06 4-4*07 3*02 3-16*02 4Omi-08 1-46*01, or 4*02 6-13*01 12 1-46*03 Omi-09 3-30*01 3*02 4-17*01 6Omi-12 1-58*02 3*02 2-2*01 12 Omi-16 3-66*02 4*02 2-15*01 9 Omi-173-66*02 4*02 6-19*01 7 Omi-18 3-53*01 6*02 4-11*01 11 Omi-20 3-66*026*02 5-12*01 11 Omi-23 4-31*03 4*02 3-22*01 6 Omi-24 1-69*06 4*023-16*02 9 Omi-25 3-9*01 6*02 3-16*01 6 Omi-26 1-18*01 4*02 1-26*01 12Omi-27 3-66*01 , or 6*02 6-19*01 8 3-66*04 Omi-28 3-66*01 , or 4*023-16*01 4 3-66*04 Omi-29 3-53*04 6*02 2-15*01 11 Omi-30 1-69*06 6*022-15*01 10 Omi-31 1-69*06 6*02 3-16*01 11 Omi-32 3-33*01, or 4*022-21*02 6 3-33*06 Omi-33 3-33*01, or 4*02 2-21*02 10 3-33*06 Omi-341-69*06, or 4*02 2-2*01 10 1-69*14 Omi-35 3-9*01 6*02 2-2*02 5 Omi-363-66*02 4*02 2-15*01 9 Omi-38 1-69*09 3*01 1-26*01 16 Omi-39 3-43*016*03 2-2*01 8 Omi-41 1-18*04 4*02 3-9*01 11 Omi-42 3-9*01 6*02 6-19*01 7Light Chain #Amino acid mAbs K/λ V-GENE J-GENE substitutions Omi-02 K3-20*01 5*01 9 Omi-03 K 3-20*01 2*01 10 Omi-06 K 1-39*01, or 4*01 91D-39*01 Omi-08 λ 1-40*02 1*01 13 Omi-09 λ 3-25*02 2*01, or 14 3*01Omi-12 K 3-20*01 1*01 9 Omi-16 K 3-20*01 2*01 10 Omi-17 K 3-20*01 2*0110 Omi-18 λ 3-21*02 1*01 10 Omi-20 K 1-9*01 4*02 ( ) 9 Omi-23 K 1-NL1*011*01 10 Omi-24 K 3-15*01 1*01 10 Omi-25 K 1-39*01, or 2*01 9 1D-39*01Omi-26 λ 1-36*01 3*02 11 Omi-27 K 1-6*01 2*01 9 Omi-28 K 3-20*01 1*01 9Omi-29 2-14*01, or 3*02 10 2-14*03 Omi-30 λ 1-44*01 3*02 11 Omi-31 λ1-44*01 3*02 11 Omi-32 K 3-20*01 4*01 10 Omi-33 K 3-20*01 4*01 4 Omi-34λ 1-40*01 1*01 12 Omi-35 λ 3-21*02 2*01, or 11 3*01 Omi-36 K 3-20*012*01 5 Omi-38 K 1-5*01 5*01 6 Omi-39 K 4-1*01 3*01 5 Omi-41 K 4-1*012*02 ( ) 5 Omi-42 λ 2-8*01 2*01, or 8 3*01 or 3*02

TABLE 18 IC50 titres of 22 Omicron SARS-CoV-2-specific human mAbs orcommercial mAbs against various SARS-CoV-2 strains. IC50 (ug/ml) mAbsVictoria Alpha Beta Gamma Delta BA.1 BA.1.1 BA.2 Omi-02 0.015 ± 0.014 ±0.009 ± 0.004 ± 0.014 ± 0.013 ± 0.015 ± 0.040 ± 0.001 0.005 0.000 0.0000.003 0.001 0.001 0.021 Omi-03 0.007 ± 0.012 ± 0.009 ± 0.004 ± 0.004 ±0.009 ± 0.015 ± 0.028 ± 0.000 0.007 0.001 0.000 0.000 0.002 0.000 0.002Omi-06 0.007 ± 0.011 ± 0.012 ± 0.010 ± 5.040 ± 0.054 ± 1.505 ± 0.238 ±0.001 0.002 0.000 0.003 0.747 0.005 0.341 0.007 Omi-08 0.014 ± 0.022 ±0.007 ± 0.024 ± 0.048 ± 0.008 ± 0.007 ± 1.510 ± 0.007 0.002 0.000 0.0070.012 0.004 0.001 0.683 Omi-09 0.004 ± 0.002 ± 1.218 ± 2.373 ± 0.008 ±0.011 ± 0.017 ± 0.034 ± 0.001 0.000 0.324 1.008 0.002 0.005 0.003 0.010Omi-12 0.005 ± 0.003 ± 0.006 ± 0.003 ± 0.003 ± 0.004 ± 0.009 ± 0.010 ±0.000 0.001 0.001 0.000 0.000 0.001 0.001 0.001 Omi-16 0.016 ± 0.022 ±0.018 ± 0.022 ± 0.016 ± 0.019 ± 0.027 ± 0.067 ± 0.002 0.009 0.004 0.0070.002 0.003 0.007 0.021 Omi-17 0.066 ± 0.098 ± 0.021 ± 0.021 ± 0.074 ±0.028 ± 0.026 ± 0.095 ± 0.015 0.027 0.007 0.007 0.019 0.005 0.001 0.008Omi-18 0.041 ± 0.038 ± 0.018 ± 0.016 ± 0.025 ± 0.006 ± 0.006 ± 0.007 ±0.005 0.008 0.006 0.004 0.000 0.003 0.001 0.001 Omi-20 0.012 ± 0.023 ±0.019 ± 0.019 ± 0.008 ± 0.043 ± 0.032 ± 0.022 ± 0.002 0.004 0.009 0.0060.001 0.012 0.002 0.005 0mi-23 0.005 ± 0.009 ± 0.020 ± 0.018 ± 0.006 ±0.044 ± 0.03 ± 0.028 ± 0.002 0.004 0.005 0.006 0.002 0.013 0.001 0.001Omi-24 0.005 ± 0.008 ± 0.006 ± 0.010 ± >10 0.007 ± 0.035 ± 0.008 ± 0.0010.003 0.001 0.005 0.001 0.010 0002 Omi-25 0.003 ± 0.007 ± 0.059 ± 0.257± 0.006 ± 0.046 ± 0.138 ± 0.056 ± 0.001 0.001 0.007 0.079 0.002 0.0150.046 0.030 Omi-26 0.005 ± 0.010 ± 0.055 ± 0.214 ± 0.005 ± 0.034 ± 0.055± 0.03 ± 0.000 0.003 0.020 0.046 0.001 0.000 0.030 0.011 Omi-27 0.026 ±0.032 ± 0.019 ± 0.017 ± 0.010 ± 0.091 ± 0.239 ± 0.039 ± 0.001 0.0120.006 0.006 0.001 0.050 0.052 0.006 Omi-28 0.028 ± 0.028 ± 0.019 ± 0.033± 0.018 ± 0.032 ± 0.075 ± 0.047 ± 0.004 0.001 0.010 0.008 0.002 0.0090.032 0.010 Omi-29 0.044 ± 0.066 ± 0.048 ± 0.040 ± 0.029 ± 0.036 ± 0.052± 0.192 ± 0.002 0.034 0.020 0.007 0.004 0.003 0.004 0.021 Omi-30 0.109 ±0.043 ± 0.028 ± 0.038 ± >10 0.058 ± 0.084 ± 0.045 ± 0.035 0.016 0.0090.004 0.008 0.021 0.010 Omi-31 0.007 ± 0.020 ± 0.011 ± 0.017 ± >10 0.010± 0.017 ± 0.083 ± 0.001 0.003 0.005 0.006 0.002 0,009 0.040 Omi-32 0.032± 0.102 ± 0.460 ± 0.430 ± 0.012 ± 0.024 ± 4.642 ± 1.899 ± 0.016 0.0410.092 0.012 0.002 0.011 0.283 0.280 Omi-33 0.028 ± 0.057 ± 0.136 ± 0.132± 0.011 ± 0.026 ± 0.113 ± 0.681 ± 0.005 0.017 0.002 0.037 0.001 0.0080.035 0.0170 Omi-34 0.003 ± 0.041 ± 0.003 ± 0.008 ± >10 0.028 ± 0.074 ±0.014 ± 0.001 0.027 0.000 0.002 0.009 0.016 0.003 Omi-35 0.057 ± 0.080 ±0.128 ± 0.136 ± 0.280 ± 0.069 ± 0.262 ± 0.082 ± 0.003 0.030 0.058 0.0240.059 0.032 0.086 0.043 Omi-36 0.056 ± 0.047 ± 0.018 ± 0.015 ± 0.026 ±0.038 ± 0.053 ± 0.105 ± 0.008 0.009 0.001 0.000 0.003 0.006 0.022 0.023Omi-38 0.001 ± 0.009 ± 0.004 ± 0.002 ± 0.004 ± 0.054 ± >10 0.027 ± 0.0000.001 0.000 0.000 0.001 0.028 0.001 Omi-39 0.015 ± 0.039 ± 0.009 ± 0.014± 0.012 ± 0.025 ± >10 0.073 ± 0.006 0.007 0.000 0.001 0.007 0.004 0.014Omi-41 0.090 ± 2.262 ± >10 0.126 ± >10 0.081 ± 0.191 ± >10 0.013 1.1990.059 0.004 0.014 Omi-42 0.016 ± 0.024 ± 0.011 ± 0.013 ± 0.019 ± 0.014 ±0.017 ± 0.031 ± 0.003 0.001 0.004 0.003 0.001 0.002 0.004 0.008REGN10987 0.032 ± 0.028 ± 0.007 ± 0.013 ± 0.017 ± >10 >10 1.847 ± 0.0070.003 0.001 0.002 0.009 1.231 REGN10933 0.004 ± 0.014 ± 3.284 ± 6.177 ±0.003 ± >10 >10 >10 0.002 0.002 2.014 1.914 0.001 AZD1061 0.013 ± 0.012± 0.014 ± 0.007 ± 0.038 ± 3.488 ± >10 0.028 ± 0.003 0.002 0.002 0.0020.006 2.085 0.014 AZD8895 0.005 ± 0.011 ± 0.046 ± 0.046 + 0.003 ± 1.152± 6.078 ± 7.702 ± 0.001 0.002 0.031 0.016 0.000 0.170 1.558 2.224AZD7442 0.009 ± 0.007 ± 0.012 ± 0.006 ± 0.005 ± 0.273 ± 3.816 ± 0.052 ±0.000 0.001 0.001 0.003 0.000 0.062 0.138 0.004 ADG10 0.006 ± 0.010 ±0.011 ± 0.003 ± 0.026 ± >10 >10 >10 0.000 0.001 0.001 0.000 0.005 ADG200.004 ± 0.006 ± 0.01 ± 0.009 ± 0.006 ± 1.104 ± 1.269 ± >10 0.001 0.0000.001 0.000 0.001 0.509 0.223 ADG30 0.007 ± 0.016 ± 0.029 ± 0.002 ±0.033 ± >10 >10 >10 0.002 0.001 0.003 0.001 0.007 Ly-CoV- 0.006 ± 0.009± >10 >10 8.311 ± >10 >10 >10 555 0.002 0.000 4.059 Ly-CoV16 0.034 ±3.225 ± >10 >10 0.012 ± >10 >10 >10 0.007 1.030 0.002 S309 0.040 ± 0.078± 0.082 ± 0.076 ± 0.113 ± 0.256 ± 1.119 ± 5.035 ± 0.005 0.069 0.0020,014 0.028 0.034 0.119 0.244

TABLE 19 X-ray data collection and structure refinement statistics forBA.1 RBD/Omi-12-Beta54 and Omi-12 Fab BA.1 RBD/Omi-12- StructureBeta54^(a) Omi-12 Fab^(a) Data collection Space group P2¹ C222¹ Celldimensions a, b, c (Å) 95.7, 156.3, 122.4 65.0, 210.1, 85.9 α, β, γ (°)90, 90.3, 90 90, 90, 90 Resolution (Å)   78-5.50 (5.60-5.50)   33-2.08(2.12-2.08) R^(merge) 0.641 (—)   0.179 (—)   R^(pim) 0.259 (0.919)0.052 (1.151) I/σ(I) 2.1 (0.4) 6.2 (0.2) CC^(1/2) 0.849 (0.332) 0.994(0.255) Completeness (%)  100 (98.2) 93.3 (62.9) Redundancy 7.1 (7.4)12.1 (6.8)  Refinement Resolution (Å) 78-5.50^(c) 53-2.08 No.reflections 11051/615  29710/1547  R^(work)/R^(free) 0.285/0.2850.241/0.267 No. atoms Protein 16328 3320 Ligand/ion/water 133 B factors(Å²) Protein 248 59 Ligand/ion/water 74 r.m.s. deviations Bond lengths(Å) 0.010 0.002 Bond angles (°) 0.7 0.6 ªOmi12 is glycosylated at N102of the heavy chain. ^(b)Values in parentheses are for highest-resolutionshell. ^(c)Rigid body and group B-factor refinement only.

TABLE 20 Pseudoviral assays comparing BA.4 neutralization withneutralization of BA.1, BA.1.1, BA.2 and BA.3 IC50 (μg/mL) PseudovirusVictoria BA.1 BA.1.1 BA.2 BA.3 BA.4 Omi-02 0.002 ± 0.001 0.004 ± 0.0010.004 ± 0.001 0.003 ± 0.001 0.019 ± 0.007 >10 Omi-03 0.003 ± 0.000 0.005± 0.002 0.003 ± 0.001 0.008 ± 0.001 0.022 ± 0.003 0.017 ± 0.005 Omi-060.007 ± 0.000 0.017 ± 0.003 0.139 ± 0.033 0.039 ± 0.008 0.696 ±0.106 >10 Omi-08 0.008 ± 0.004 0.003 ± 0.000 0.002 ± 0.000 0.114 ± 0.0450.032 ± 0.001 0.086 ± 0.005 Omi-09 0.006 ± 0.002 0.005 ± 0.000 0.005 ±0.002 0.008 ± 0.002 0.017 ± 0.002 0.166 ± 0.007 Omi-12 0.006 ± 0.0020.002 ± 0.000 0.002 ± 0.001 0.003 ± 0.001 0.006 ± 0.001 0.429 ± 0.060Omi-16 0.014 ± 0.003 0.012 ± 0.002 0.011 ± 0.003 0.034 ± 0.012 0.111 ±0.008 0.029 ± 0.007 Omi-17 0.023 ± 0.011 0.018 ± 0.012 0.022 ± 0.0090.060 ± 0.004 0.123 ± 0.002 0.028 ± 0.001 Omi-18 0.008 ± 0.003 0.002 ±0.000 0.002 ± 0.000 0.005 ± 0.000 0.006 ± 0.002 0.005 ± 0.001 Omi-200.009 ± 0.002 0.006 ± 0.001 0.005 ± 0.001 0.015 ± 0.003 0.020 ± 0.0040.014 ± 0.006 Omi-23 0.005 ± 0.002 0.029 ± 0.006 0.023 ± 0.12  0.019 ±0.005 0.011 ± 0.000 >10 Omi-24 0.005 ± 0.000 0.006 ± 0.002 0.054 ± 0.0150.007 ± 0.001 0.009 ± 0.002 >10 Omi-25 0.005 ± 0.001 0.023 ± 0.005 0.027± 0.005 0.024 ± 0.004 0.050 ± 0.004 >10 Omi-26 0.002 ± 0.001 0.006 ±0.002 0.005 ± 0.001 0.013 ± 0.001 0.018 ± 0.002 >10 Omi-27 0.008 ± 0.0030.026 ± 0.006 0.034 ± 0.009 0.034 ± 0.005 0.026 ± 0.007 0.069 ± 0.023Omi-28 0.022 ± 0.000 0.011 ± 0.004 0.009 ± 0.002 0.008 ± 0.000 0.019 ±0.000 0.028 ± 0.009 Omi-29 0.014 ± 0.006 0.017 ± 0.003 0.016 ± 0.0090.056 ± 0.014 0.064 ± 0.017 0.396 ± 0.007 Omi-30 0.053 ± 0.010 0.029 ±0.002 0.031 ± 0.012 0.013 ± 0.002 0.015 ± 0.003 >10 Omi-31 0.012 ± 0.0020.008 ± 0.003 0.008 ± 0.004 0.011 ± 0.002 0.013 ± 0.004 >10 Omi-32 0.010± 0.006 0.017 ± 0.000 >10 2.682 ± 0.553 1.018 ± 0.139 0.035 ± 0.016Omi-33 0.027 ± 0.011 0.014 ± 0.005 0.042 ± 0.018 0.068 ± 0.022 0.133 ±0.021 0.013 ± 0.004 Omi-34 0.007 ± 0.004 0.008 ± 0.001 0.062 ± 0.0040.009 ± 0.003 0.014 ± 0.000 >10 Omi-35 0.021 ± 0.003 0.058 ± 0.006 0.381± 0.061 0.094 ± 0.004 0.044 ± 0.018 1.687 ± 0.441 Omi-36 0.022 ± 0.0040.009 ± 0.003 0.009 ± 0.003 0.030 ± 0.014 0.178 ± 0.048 0.024 ± 0.006Omi-38 0.015 ± 0.004 0.024 ± 0.015 >10 0.005 ± 0.000 0.008 ± 0.002 0.005± 0.001 Omi-39 0.014 ± 0.002 0.009 ± 0.004 >10 0.026 ± 0.011 0.014 ±0.001 0.035 ± 0.003 Omi-41 >10 0.053 ± 0.028 0.037 ± 0.002 >10 0.032 ±0.007 >10 Omi-42 0.013 ± 0.004 0.007 ± 0.004 0.006 ± 0.002 0.021 ± 0.0110.025 ± 0.012 0.013 ± 0.001

TABLE 21 Activity of commercial antibodies against BA.4 and BA.5 IC50(μg/mL) Pseudovirus Victoria BA.1 BA.1.1 BA.2 BA.3 BA.4 REGN10987 0.002± 0.001 >10 >10 0.616 ± 0.347 >10 >10 REGN10933 0.001 ±0.002 >10 >10 >10 >10 >10 AZD1061 0.002 ± 0.001 0.308 ± 0.058 >10 0.008± 0.003 0.019 ± 0.007 0.015 ± 0.004 AZD8895 0.001 ± 0.000 0.246 ± 0.0270.100 ± 0.053 1.333 ± 0.317 >10 >10 AZD7442 0.001 ± 0.000 0.232 ± 0.1130.806 ± 0.093 0.008 ± 0.001 0.065 ± 0.011 0.065 ± 0.007 ADG10 0.007 ±0.002 >10 >10 >10 >10 >10 ADG20 0.003 ± 0.002 0.348 ± 0.169 0.253 ±0.070 >10 >10 >10 ADG30 0.014 ± 0.006 >10 >10 >10 >10 >10 Ly-CoV-5550.002 ± 0.000 >10 >10 >10 >10 >10 Ly-CoV16 0.014 ±0.010 >10 >10 >10 >10 >10 S309 0.130 ± 0.030 0.094 ± 0.008 0.138 ± 0.0200.638 ± 0.107 0.228 ± 0.009 1.041 ± 0.072

TABLE 22 IC50 of BA.1 mAbs against PV BA.2.75 and BA.2 + N460K mAbsVictoria BA.1 BA.1.1 BA.2 BA.3 BA.4/5 BA.2.75 BA.2 + N460K Omi-02 0.002± 0.001 0.004 ± 0.001 0.004 ± 0.001 0.003 ± 0.001 0.019 ± 0.007 >100.009 ± 0.002 0.025 ± 0.003 Omi-03 0.003 ± 0.000 0.005 ± 0.002 0.003 ±0.001 0.008 ± 0.001 0.022 ± 0.003 0.037 ± 0.005 0.017 ± 0.000 0.401 ±0.026 (3-53) Omi-06 0.007 ± 0.000 0.017 ± 0.003 0.139 ± 0.033 0.039 ±0.008 0.696 ± 0.306 >10 0.063 ± 0.005 0.026 ± 0.002 Omi-08 0.008 ± 0.0040.003 ± 0.000 0.002 ± 0.000 0.314 ± 0.045 0.032 ± 0.001 0.086 ± 0.0050.030 ± 0.002 0.552 ± 0.090 Omi-09 0.005 ± 0.002 0.005 ± 0.000 0.005 ±0.002 0.008 ± 0.002 0.017 ± 0.002 0.166 ± 0.007 0.003 ± 0.000 0.020 ±0.002 Omi-12 0.006 ± 0.002 0.002 ± 0.000 0.002 ± 0.001 0.003 ± 0.0010.006 ± 0.001 0.429 ± 0.060 0.003 ± 0.001 0.011 ± 0.002 Omi-16 0.014 ±0.003 0.012 ± 0.002 0.011 ± 0.003 0.034 ± 0.012 0.111 ± 0.008 0.029 ±0.007 >10 >10 (3-56) Omi-17 0.022 ± 0.011 0.018 ± 0.012 0.022 ± 0.0050.060 ± 0.004 0.123 ± 0.002 0.028 ± 0.001 0.255 ± 0.169 >10 (3-56)Omi-18 0.008 ± 0.003 0.002 ± 0.000 0.002 ± 0.000 0.005 ± 0.000 0.006 ±0.002 0.005 ± 0.001 0.035 ± 0.007 0.014 ± 0.002 (3-53) Omi-20 0.009 ±0.002 0.006 ± 0.001 0.005 ± 0.001 0.015 ± 0.003 0.020 ± 0.004 0.014 ±0.006 0.178 ± 0.075 0.315 ± 0.142 (3-56) Omi-23 0.005 ± 0.002 0.029 ±0.005 0.023 ± 0.12  0.019 ± 0.005 0.011 ± 0.000 >10 0.011 ± 0.006 0.022± 0.005 Omi-24 0.005 ± 0.003 0.005 ± 0.002 0.054 ± 0.015 0.007 ± 0.0010.009 ± 0.002 >10 0.008 ± 0.004 0.014 ± 0.000 Omi-25 0.005 ± 0.001 0.023± 0.005 0.027 ± 0.005 0.024 ± 0.004 0.050 ± 0.004 >10 0.014 ± 0.0050.050 ± 0.010 Omi-26 0.002 ± 0.001 0.005 ± 0.002 0.005 ± 0.001 0.013 ±0.001 0.018 ± 0.002 >10 0.010 ± 0.004 0.010 ± 0.000 Omi-27 0.008 ± 0.0030.026 ± 0.006 0.034 ± 0.009 0.034 ± 0.035 0.025 ± 0.007 0.069 ± 0.0236.672 ± 4.465 >10 (3-56) Omi-28 0.022 ± 0.000 0.011 ± 0.004 0.009 ±0.002 0.008 ± 0.000 0.019 ± 0.000 0.028 ± 0.009 0.133 ± 0.082 0.103 ±0.048 (3-56) Omi-29 0.014 ± 0.006 0.017 ± 0.003 0.018 ± 0.009 0.056 ±0.014 0.064 ± 0.017 0.396 ± 0.007 >10 >10 (3-53) Omi-30 0.012 ± 0.0020.008 ± 0.003 0.006 ± 0.004 0.011 ± 0.002 0.015 ± 0.003 >10

  ± 0.002 0.018 ± 0.001 Omi-31 0.376 ± 0.090 0.029 ± 0.002 0.031 ± 0.0120.013 ± 0.002 0.018 ± 0.004 >10 0.014 ± 0.008 0.015 ± 0.001 Omi-32 0.010± 0.005 0.017 ± 0.000 >10 2.682 ± 0.553 1.018 ± 0.139 0.035 ± 0.0160.354 ± 0.064 2.341 ± 0.282 Omi-33 0.027 ± 0.011 0.014 ± 0.005 0.042 ±0.018 0.058 ± 0.022 0.133 ± 0.021 0.013 ± 0.004 0.053 ± 0.005 0.490 ±0.156 Omi-34 0.007 ± 0.004 0.008 ± 0.001 0.062 ± 0.004 0.009 ± 0.0030.014 ± 0.000 >10 0.005 ± 0.000 0.020 ± 0.001 Omi-35 0.018 ± 0.004 0.058± 0.005 0.381 ± 0.051 0.054 ± 0.004 0.044 ± 0.018 1.657 ± 0.441 0.020 ±0.000 0.056 ± 0.012 Omi-36 0.022 ± 0.004 0.009 ± 0.003 0.009 ± 0.0030.030 ± 0.014 0.178 ± 0.048 0.024 ± 0.006 >10 >10 (3-66) Omi-38 0.015 ±0.004 0.024 ± 0.015 >10 0.005 ± 0.000 0.008 ± 0.002 0.005 ± 0.001 0.011± 0.005 0.010 ± 0.001 Omi-39 0.015 ± 0.002 0.009 ± 0.004 >10 0.026 ±0.011 0.014 ± 0.001 0.035 ± 0.003 0.027 ± 0.009 0.045 ± 0.017 Omi-41 >100.053 ± 0.028 0.037 ± 0.002 >10 0.032 ± 0.007 >10 >10 >10 Omi-42 0.013 ±0.004 0.007 ± 0.004 0.006 ± 0.002 0.021 ± 0.011 0.025 ± 0.012 0.013 ±0.001 0.003 ± 0.000 0.007 ± 0.002

indicates data missing or illegible when filed

TABLE 23 IC50 of commercial mAbs against PV BA.2.75 IC50 (μg/mL)Pseudovisus Victoria BA.1 BA.1.1 BA.2 BA.3 BA.4/5 BA.2.75 REGN109930.002 ± 0.001 >10 >10 0.616 ± 0.347 >10 >10 >10 REGN11093 0.001 ±0.002 >10 >10 >10 >10 >10 >10 AZD1061 0.002 ± 0.001 0.308 ± 0.058 >100.008 ± 0.003 0.019 ± 0.007 0.015 ± 0.004 0.021 ± 0.002 AZD8895 0.001 ±0.003 0.246 ± 0.027 0.100 ± 0.317 1.335 ± 0.317 >10 >10 0.008 ±  

AZD7442 0.001 ± 0.000 0.252 ± 0.115 0.805 ± 0.095 0.008 ± 0.001 0.065 ±0.011 0.065 ± 0.007 0.017 ± 0.003 ADG10 0.007 ±0.002 >10 >10 >10 >10 >10 >10 ADG20 0.008 ± 0.002 0.348 ± 0.159 0.253 ±0.070 >10 >10 >10 >10 ADG30 0.014 ± 0.006 >10 >10 >10 >10 >10 >10Ly-CoV555 0.002 ± 0.000 >10 >10 >10 >10 >10 >10 Ly-CoV16 0.014 ±0.010 >10 >10 >10 >10 >10 >10 Ly-CoV1404 0.001 ± 0.000 0.002 ± 0.0000.001 ± 0.000 0.002 ± 0.000 0.002 ± 0.000 0.002 ± 0.000 0.002 ± 0.0005309 0.079 ± 0.027 0.113 ± 0.006 0.142 ± 0.012 0.538 ± 0.154 0.311 ±0.023 0.689 ± 0.041 0.202 ± 0.017

indicates data missing or illegible when filed

TABLE 24 IC50 (μg/ml) mAbs BA.2 BA.2 + D339H BA.2 + R493Q BA.2 + G446SBA.2. + N460K BA.2.75 Omi02 0.003 ± 0.000 0.007 ± 0.003 0.003 ± 0.0000.007 ± 0.002 0.025 ± 0.003 0.009 ± 0.002 Omi03 0.008 ± 0.001 0.006 ±0.000 0.002 ± 0.001 0.005 ± 0.001 0.401 ± 0.026 0.017 ± 0.000 Omi060.039 ± 0.008 0.012 ± 0.002 0.023 ± 0.010 0.087 ± 0.002 0.026 ± 0.0020.063 ± 0.005 Omi08 0.114 ± 0.045 0.250 ± 0.009 0.194 ± 0.020 0.017 ±0.001 0.552 ± 0.090 0.036 ± 0.002 Omi09 0.008 ± 0.002 0.005 ± 0.0010.003 ± 0.000 0.006 ± 0.001 0.010 ± 0.002 0.003 ± 0.000 Omi12 0.003 ±0.001 0.003 ± 0.001 0.001 ± 0.000 0.003 ± 0.001 0.011 ± 0.002 0.003 ±0.001 Omi16 0.034 ± 0.012 0.014 ± 0.004 0.008 ± 0.003 0.018 ±0.004 >10 >10 Omi17 0.060 ± 0.004 0.036 ± 0.015 0.013 ± 0.001 0.038 ±0.002 >10 0.255 ± 0.169 Omi18 0.005 ± 0.000 0.003 ± 0.000 0.004 ± 0.0000.003 ± 0.000 0.014 ± 0.002 0.035 ± 0.007 Omi20 0.015 ± 0.003 0.007 ±0.000 0.005 ± 0.001 0.005 ± 0.001 0.315 ± 0.142 0.178 ± 0.075 Omi230.019 ± 0.005 0.006 ± 0.000 0.007 ± 0.000 0.010 ± 0.002 0.022 ± 0.0050.011 ± 0.006 Omi24 0.007 ± 0.001 0.005 ± 0.001 0.004 ± 0.000 0.005 ±0.000 0.014 ± 0.000 0.008 ± 0.004 Omi25 0.024 ± 0.004 0.016 ± 0.0030.007 ± 0.002 0.022 ± 0.000 0.050 ± 0.010 0.014 ± 0.005 Omi26 0.013 ±0.001 0.007 ± 0.002 0.008 ± 0.001 0.008 ± 0.002 0.010 ± 0.000 0.010 ±0.004 Omi27 0.034 ± 0.006 0.007 ± 0.001 0.007 ± 0.001 0.011 ± 0.001 >106.672 ± 4.466 Omi28 0.008 ± 0.000 0.009 ± 0.001 0.010 ± 0.001 0.014 ±0.000 0.103 ± 0.048 0.133 ± 0.082 Omi29 0.056 ± 0.014 0.018 ± 0.0060.042 ± 0.012 0.024 ± 0.002 >10 >10 Omi30 0.013 ± 0.002 0.006 ± 0.0010.002 ± 0.000 0.003 ± 0.000 0.018 ± 0.001 0.008 ± 0.002 Omi31 0.011 ±0.002 0.005 ± 0.001 0.003 ± 0.000 0.005 ± 0.001 0.015 ± 0.001 0.014 ±0.008 Omi32 2.614 ± 0.533 0.683 ± 0.179 0.312 ± 0.008 0.330 ± 0.0102.341 ± 0.282 0.354 ± 0.064 Omi33 0.070 ± 0.024 0.177 ± 0.035 0.063 ±0.008 0.043 ± 0.016 0.490 ± 0.156 0.053 ± 0.006 Omi34 0.009 ± 0.0030.004 ± 0.000 0.002 ± 0.000 0.002 ± 0.000 0.020 ± 0.001 0.005 ± 0.000Omi35 0.092 ± 0.004 0.012 ± 0.003 0.017 ± 0.011 0.014 ± 0.006 0.056 ±0.012 0.020 ± 0.000 Omi36 0.030 ± 0.014 0.036 ± 0.002 0.013 ± 0.0030.067 ± 0.015 >10 >10 Omi38 0.005 ± 0.000 0.011 ± 0.000 0.003 ± 0.0010.010 ± 0.000 0.010 ± 0.001 0.011 ± 0.005 Omi39 0.026 ± 0.011 0.012 ±0.002 0.021 ± 0.007 0.009 ± 0.002 0.045 ± 0.017 0.027 ± 0.009Omi41 >10 >10 >10 >10 >10 >10 Omi42 0.021 ± 0.011 0.011 ± 0.002 0.006 ±0.001 0.016 ± 0.002 0.007 ± 0.002 0.003 ± 0.000

TABLE 25 X-ray data collection and structure refinement statistics forBA.2.75 RBD/ACE2 Structure BA.2.75 RBD/ACE2 Data collection Space groupP4₁2₁2 Cell dimensions a, b, c (Å) 105.3, 105.3, 220.8 a, b, g (º) 90,90, 90 Resolution (Å)  76-2.85 (2.80-2.85)ª R_(merge) 0.443 (—)  R_(pim) 0.086 (1.401) I/s(I) 7.6 (0.4) CC_(1/2) 0.971 (0.279)Completeness (%) 99.8 (96.9) Redundancy 26.8 (25.7) RefinementResolution (Å) 76-2.85 No. reflections 2089/1439 R_(work)/R_(free)0.217/0.265 No. atoms Protein 6464 Ligand/ion/water 167 B factors (Å²)Protein 86 Ligand/ion/water 108 r.m.s. deviations Bond lengths (Å) 0.002Bond angles (º) 0.4 ^(a)Values in parentheses are for highest-resolutionshell.

TABLE 26 IC50 values for Omicron mAbs IC50 (μg/ml) mAbs BA.2 BA.2.11BA.2.12.1 BA.2.13 Omi02 0.003 ± 0.000 0.004 ± 0.001 0.005 ± 0.001 0.004± 0.000 Omi03 0.008 ± 0.001 0.005 ± 0.002 0.003 ± 0.001 0.007 ± 0.005Omi06 0.039 ± 0.008 0.000 ± 0.000 0.616 ± 0.123 0.046 ± 0.024 Omi080.114 ± 0.045 0.099 ± 0.020 0.358 ± 0.076 0.117 ± 0.009 Omi09 0.008 ±0.002 0.016 ± 0.005 0.015 ± 0.003 0.022 ± 0.002 Omi12 0.003 ± 0.0010.002 ± 0.000 0.001 ± 0.000 0.003 ± 0.000 Omi16 0.034 ± 0.012 0.017 ±0.004 0.011 ± 0.005 0.008 ± 0.000 Omi17 0.060 ± 0.004 0.022 ± 0.0080.034 ± 0.001 0.016 ± 0.001 Omi18 0.005 ± 0.000 0.002 ± 0.000 0.002 ±0.000 0.002 ± 0.001 Omi20 0.015 ± 0.003 0.007 ± 0.004 0.007 ± 0.0000.006 ± 0.000 Omi23 0.019 ± 0.005 0.009 ± 0.003 0.006 ± 0.002 0.005 ±0.001 Omi24 0.007 ± 0.001 0.000 ± 0.000 0.450 ± 0.140 0.008 ± 0.000Omi25 0.024 ± 0.004 0.007 ± 0.001 0.009 ± 0.002 0.010 ± 0.000 Omi260.013 ± 0.001 0.007 ± 0.003 0.002 ± 0.000 0.006 ± 0.000 Omi27 0.034 ±0.006 0.005 ± 0.001 0.003 ± 0.001 0.006 ± 0.000 Omi28 0.008 ± 0.0000.007 ± 0.000 0.005 ± 0.000 0.009 ± 0.001 Omi29 0.056 ± 0.014 0.011 ±0.001 0.007 ± 0.001 0.012 ± 0.001 Omi30 0.013 ± 0.002 10 0.086 ± 0.0260.020 ± 0.002 Omi31 0.011 ± 0.002 10 0.089 ± 0.035 0.008 ± 0.004 Omi322.614 ± 0.53  0.070 ± 0.008 10 0.503 ± 0.080 Omi33 0.070 ± 0.024 0.008 ±0.002 0.086 ± 0.045 0.055 ± 0.007 Omi34 0.009 ± 0.003 10 0.408 ± 0.1400.003 ± 0.001 Omi35 0.092 ± 0.003 0.667 ± 0.104 0.188 ± 0.074 0.016 ±0.004 Omi36 0.030 ± 0.014 0.051 ± 0.027 0.026 ± 0.011 0.020 ± 0.004Omi38 0.005 ± 0.000 0.004 ± 0.001 0.003 ± 0.000 0.003 ± 0.001 Omi390.026 ± 0.011 0.018 ± 0.003 0.068 ± 0.008 0.025 ± 0.007 Omi42 0.021 ±0.011 0.009 ± 0.003 0.012 ± 0.001 0.009 ± 0.001

TABLE 27 Primer sequences used to generate pseudoviruses.Related to Plasmid construction andpseudotyped lentiviral partic les production. Primer Sequence (5′ to 3′)BA.2.11 LA52R_F GGAGGCAATTACAATTACC GGTACAGACTGTTCAGAAAG L452R_RCTTTCTGAACAGTCTGTACC GGTAATTGTAATTGCCTCC BA.2.12.1 LA52Q_RCTTTCTGAACAGTCTGTAC TGGTAATTGTAATTGCCTCC L452Q_F GGAGGCAATTACAATTACCAGTACAGACTGTTCAGAAAG S704L_F GAGCCTGGGGGCCGAGAATC TAGTGGCCTACAGCAATAAT AGS704L_R CTATTATTGCTGTAGGCCAC TAGATTCTCGGCGCCCAGGC TC 8A.2.13 L452M_FGTTGGAGGCAATTACAATTAC ATGTACAGACTGTTCAGAAAGA L452M_RTCTTTCTGAACAGTCTGTACA TGTAATTGTAATTGCCTCCAAC

TABLE 28 X-ray data collection and structure refinement statistics aValues in parentheses are for highest-resolution shell. StructureBA.2.12.1 RBD/Beta-27/NbCl Data collection Space group C2 Celldimensions a, b, c (Å) 186.8, 100.0, 56.5 α, β, γ (°) 90, 104.1, 90Resolution (Å)  55-2.38 (2.42-2.38)^(a) R_(merge) 0.240 (—)   R_(pim)0.071 (1.366) I/σ(I) 6.3 (0.3) CC_(1/2) 0.988 (0.13)  Completeness (%)94.8 (67.7) Redundancy 11.2 (4.4)  Refinement Resolution (Å) 55-2.38 No.reflections 35221/1842  R_(work)/R_(free) 0.186/0.233 No. atoms Protein5723 Ligand/ion/water 259 B factors (Å²) Protein 58 Ligand/ion/water 60r.m.s. deviations Bond lengths (Å) 0.002 Bond angles (º) 0.5

TABLE 29 IC50 values for Omicron mAbs and commercial monoclonals a mAbsVictoria BA.1 BA.1.1 BA.2 BA.4/5 BA.4.6 Omi-02 0.002 ± 0.001 0.004 ±0.001 0.004 ± 0.001 0.003 ± 0.001 >10 >10 Omi-03 (3-53) 0.003 ± 0.0000.005 ± 0.002 0.003 ± 0.001 0.008 ± 0.001 0.017 ± 0.005 0.006 ± 0.002Omi-06 0.007 ± 0.000 0.017 ± 0.003 0.139 ± 0.033 0.039 ± 0.008 >10 >10Omi-08 0.008 ± 0.004 0.003 ± 0.000 0.002 ± 0.000 0.114 ± 0.045 0.086 ±0.005 0.033 ± 0.002 Omi-09 0.006 ± 0.002 0.005 ± 0.000 0.005 ± 0.0020.008 ± 0.002 0.166 ± 0.007 0.108 ± 0.009 Omi-12 0.006 ± 0.002 0.002 ±0.000 0.002 ± 0.001 0.003 ± 0.001 0.429 ± 0.060 0.074 ± 0.018 Omi-16(3-66) 0.014 ± 0.003 0.012 ± 0.002 0.011 ± 0.003 0.034 ± 0.012 0.029 ±0.007 0.007 ± 0.001 Omi-17 (3-66) 0.023 ± 0.011 0.018 ± 0.012 0.022 ±0.009 0.060 ± 0.004 0.028 ± 0.001 0.039 ± 0.008 Omi-18 (3-53) 0.008 ±0.003 0.002 ± 0.000 0.002 ± 0.000 0.005 ± 0.000 0.005 ± 0.001 0.006 ±0.001 Omi-20 (3-66) 0.009 ± 0.002 0.006 ± 0.001 0.005 ± 0.001 0.015 ±0.003 0.014 ± 0.006 0.008 ± 0.003 Omi-23 0.005 ± 0.002 0.029 ± 0.0060.023 ± 0.12  0.019 ± 0.005 >10 >10 Omi-24 0.005 ± 0.000 0.005 ± 0.0020.054 ± 0.015 0.007 ± 0.001 >10 >10 Omi-25 0.005 ± 0.001 0.023 ± 0.0050.027 ± 0.005 0.024 ± 0.004 >10 >10 Omi-26 0.002 ± 0.001 0.006 ± 0.0020.005 ± 0.001 0.013 ± 0.001 >10 >10 Omi-27 (3-66) 0.008 ± 0.003 0.026 ±0.006 0.034 ± 0.009 0.034 ± 0.005 0.069 ± 0.023 0.023 ± 0.002 Omi-28(3-66) 0.022 ± 0.000 0.011 ± 0.004 0.009 ± 0.002 0.008 ± 0.000 0.028 ±0.009 0.035 ± 0.011 Omi-29 (3-53) 0.014 ± 0.006 0.017 ± 0.003 0.016 ±0.009 0.056 ± 0.014 0.396 ± 0.007 0.170 ± 0.030 Omi-30 0.012 ± 0.0020.008 ± 0.003 0.008 ± 0.004 0.011 ± 0.002 >10 >10 Omi-31 0.376 ± 0.0900.029 ± 0.002 0.031 ± 0.012 0.013 ± 0.002 >10 >10 Omi-32 0.010 ± 0.0060.017 ± 0.000 >10 2.682 ± 0.553 0.035 ± 0.016 >10 Omi-33 0.027 ± 0.0110.014 ± 0.005 0.042 ± 0.018 0.068 ± 0.022 0.013 ± 0.004 >10 Omi-34 0.007± 0.004 0.008 ± 0.001 0.062 ± 0.004 0.009 ± 0.003 >10 >10 Omi-35 0.016 ±0.004 0.058 ± 0.006 0.381 ± 0.051 0.094 ± 0.004 1.587 ± 0.441 >10 Omi-36(3-66) 0.022 ± 0.004 0.009 ± 0.003 0.009 ± 0.003 0.090 ± 0.014 0.024 ±0.006 0.029 ± 0.001 Omi-38 0.015 ± 0.004 0.024 ± 0.015 >10 0.005 ± 0.0000.005 ± 0.001 >10 Omi-39 0.014 ± 0.002 0.009 ± 0.004 >10 0.026 ± 0.0110.035 ± 0.003 >10 Omi-41 >10 0.053 ± 0.028 0.037 ± 0.002 >10 >10 >10Omi-42 0.013 ± 0.004 0.007 ± 0.004 0.006 ± 0.002 0.021 ± 0.011 0.013 ±0.001 0.010 ± 0.001 b IC50 (μg/mL) Pseudovirus Victoria BA.1 BA.1.1 BA.2BA.3 BA.4 BA.4.6 AZD1061 0.002 ± 0.003 0.308 ± 0.058 >10 0.008 ± 0.0080.019 ± 0.007 0.015 ± 0.004 >10 AZD8895 0.001 ± 0.000 0.246 ± 0.0270.100 ± 0.053 1.333 ± 0.317 >10 >10 >10 AZD7442 0.001 ± 0.000 0.232 ±0.113 0.806 ± 0.093 0.008 ± 0.001 0.065 ± 0.011 0.065 ± 0.007 >10REGN10987 0.002 ± 0.001 >10 >10 0.516 ± 0.347 >10 >10 >10 REGN109330.001 ± 0.002 >10 >10 >10 >10 >10 >10 ADG10 0.007 ±0.002 >10 >10 >10 >10 >10 >10 ADG20 0.003 ± 0.002 0.348 ± 0.159 0.253 ±0.070 >10 >10 >10 >10 ADG30 0.014 ± 0.005 >10 >10 >10 >10 >10 >10Ly-CoV555 0.002 ± 0.000 >10 >10 >10 >10 >10 >10 Ly-Cov16 0.014 ±0.010 >10 >10 >10 >10 >10 >10 Ly-CoV1404 0.001 ± 0.000 0.002 ± 0.0000.001 ± 0.000 0.001 ± 0.000 0.002 ± 0.000 0.002 ± 0.000 0.001 ± 0.000S309 0.079 ± 0.027 0.313 ± 0.006 0.142 ± 0.012 0.638 ± 0.154 0.311 ±0.023 0.589 ± 0.041 1.029 ± 0.098

TABLE 30 Primer sequences used to generate pseudoviruses.Related to Plasmid construction andpseudotyped lentiviral particle production. Primer Sequence (5′ to 3′)pcDNA3.1_BamHI_F GGATCCATGTTCCTGCTGACCACCAAGAG pcDNA3.1_Tag_GAATTCTCACTTCTCGAACTGAGGGTGGC S_EcoRI_R pcDNA3.1_Tag_GCCACCCTGAGTTCGAGAAGTGAGAGTTC S_EcoRI_F pcDNA3.1_BamHI_RCTCTTGGTGGTCAGCAGGAACATGGATCC BA 4 + R346T_FGTGTTCAATGCCACCACGTTCGCCAGCGT GTACG BA.4 + R345T_RCGTACACGCTGGCGAACGTGGTGGCATTG AACAG BA.4 + N6S58S_FCGGCGCCGAGTACGTGAATAGTAGCTACG AGTGCG BA.4 + N6S58S_RCGCACTCGTAGCTACTATTCACGTACTCG GCGCCG

TABLE 31 Table of SARS-CoV-2 lineages and genomic mutations Country/Example Region Date of Defining RBD early of earliest earliest Pangoissue, Lineage mutations genome Submitting scientist, laboratorysequences sequences contributor BA.A.6 BA.4/5 + R3467 EPI_ISL_Oliveratal, HOSPITAL Europe/South April 2022 #741, 32475382UNIVERSITARIO SON Africa ryhisner ESPASES BA.A.7 BA.4/5 + R3457 EPI_ISL_Iranzauen et al. NHLS/UCT South Africa/ April 2022 #777, 32644817 IsraelFedaGuell BA.7(BA.5.2.3.7) BA.4/5 R3467 EPI_ISL_ Coppens et al., LaboKinische Belgium May 2022 #827, 32810243 Biologie, 2A ryhisnerBO.1(BA.5.3.1.1.3.1.5) BA.4/5 K444T, EPI_ISL_ Howardetal, Centers forDisease Nigeria July 2022 #998, N450K 34294805 Control and PreventionDivision FedaGuell of Viral Diseases, Pathogen Discovery BO.1.3(BA.55.3.1.1.3.1.1) BO.1 + R346T EPI_ISL_ Christensen et al., Houston USAAugust 2022 #993, 14752457 Methodis Hospital FedaGuell BA.2.7.5 BA.2 +G4465, EPI_ISL_ Rhaimaratal, CSIR-NEER,  

India April 2022 #773, N450K, R498Q 

33802209 Covid-19 Testing lab Siten BA.2.75.2 BA.2.75 + R3451, EPI_ISL_Gupta et al. IL85/INSAOOG India July 2022 #965, FA86S 24250506agamediate BN.1(BA.2.75.5.2) BA.2.75 + R345T, EPI_ISL_ Sima et al.,Lifebrain CovidLabor India July 2022 #994, K356T, FA908 24801544 Gmisscornetiusenemer BA.1(BA.2.10.1.1) BA.2 + R345T, EPI_ISL_ MaitraetalNational institute of India June 2022 #935, Sikn L3681, V4459, 14366803Biomedical Genomies-INSACOG G448S, V483A, F480V BA.2.10.A BA.2 +G4485,EPI_ISL_ et al., Center for Genomics, India June 2022 #898, Sikn F485P,R498Q 

 , 18929780 Department of Microbiology, BJ 5494P Government MedicalCollege and Gaesoon Hospitals BS.1(BA.2.3.2.3) BA.2 + R345T, EPI_ISL_Sekuzuka et al, Pathogen Japan ex August 2022 #1052, L452H, N450K,34565710 Genomics Center, National Vietnam TakaKeng G475S Institute ofInfectious Diseases BA.2.3.20 K44N, N450D, EPI_ISL_ Setway et al, SAPathology USA/ August 2022 #1053, ryhisner L452M, N450K, 34725265Singapore/ E484R, R493Q 

Australia X55 BA.2 + R3457, EPI_ISL_ Nigan et al, National Public IndiaAugust 2022 #1058, L368I, V445P, 24917701 Health Laboratory, Nationalcornetiusnemer G446S, N460K, Centre for Infectious Diseases F4565, F450S

indicates data missing or illegible when filed

TABLE 32 IC50 values for BA.1 mAbs and commercial mAbs mAbs VictoriaBA.2 BA.4/5 BA.4.5 BA.2.75 BA.2.75.2 BA.2.3.20 BA.1 BA.4 + all a Omi-020.002 ± 0.001 0.003 ± 0.001 >10 >10 0.009 ± 0.002 >10 0.013 ± 0.0010.011 ± 0.001 >10 Omi-03 0.003 ± 0.000 0.008 ± 0.001 0.017 ± 0.005 0.006± 0.002 0.017 ± 0.000 0.546 ± 0.166 0.020 ± 0.007 0.014 ± 0.000 0.432 ±0.106 (3-53) Omi-06 0.007 ± 0.000 0.039 ± 0.008 >10 >10 0.063 ±0.005 >10 >10 >10 >10 Omi-08 0.008 ± 0.004 0.114 ± 0.045 0.086 ± 0.0050.033 ± 0.002 0.035 ± 0.002 0.027 ± 0.012 0.426 ± 0.024 >10 >10 Omi-090.006 ± 0.002 0.008 ± 0.002 0.166 ± 0.007 0.108 ± 0.009 0.003 ± 0.0000.012 ± 0.000 0.133 ± 0.003 >10 >10 Omi-12 0.006 ± 0.002 0.003 ± 0.0010.429 ± 0.060 0.074 ± 0.018 0.003 ± 0.001 >10 0.008 ± 0.001 0.004 ±0.000 >10 Omi-16 0.014 ± 0.003 0.034 ± 0.012 0.029 ± 0.007 0.007 ± 0.0018.666 ± 4.596 >10 1.075 ± 0.241 0.025 ± 0.000 >10 (3-66) Omi-17 0.023 ±0.011 0.060 ± 0.004 0.028 ± 0.001 0.039 ± 0.008 0.255 ± 0.169 >10 0.347± 0.123 0.030 ± 0.006 >10 (3-66) Omi-18 0.008 ± 0.003 0.005 ± 0.0000.005 ± 0.001 0.006 ± 0.001 0.035 ± 0.007 4.800 ± 0.568 0.011 ± 0.0010.005 ± 0.002 3.607 ± 0.807 (3-53) Omi-20 0.009 ± 0.002 0.015 ± 0.0030.014 ± 0.006 0.008 ± 0.003 0.178 ± 0.075 8.948 ± 3.561 0.030 ± 0.0050.009 ± 0.002 >10 (3-66) Omi-23 0.005 ± 0.002 0.019 ± 0.005 >10 >100.011 ± 0.006 >10 0.009 ± 0.003 0.024 ± 0.001 >10 Omi-24 0.005 ± 0.0000.007 ± 0.001 >10 >10 0.008 ± 0.004 4.681 ± 1.859 >10 >10 >10 Omi-250.005 ± 0.001 0.024 ± 0.004 >10 >10 0.014 ± 0.005 >10 0.025 ± 0.0040.041 ± 0.028 >10 Omi-26 0.002 ± 0.001 0.013 ± 0.001 >10 >10 0.010 ±0.004 >10 0.006 ± 0.001 0.031 ± 0.015 >10 Omi-27 0.008 ± 0.003 0.034 ±0.005 0.069 ± 0.023 0.023 ± 0.002 6.672 ± 4.466 >10 0.215 ± 0.111 0.007± 0.000 >10 (3-66) Omi-28 0.022 ± 0.000 0.008 ± 0.009 0.028 ± 0.0090.035 ± 0.011 0.133 ± 0.082 7.592 ± 0.028 0.053 ± 0.013 0.010 ±0.013 >10 (3-66) Omi-29 0.014 ± 0.005 0.056 ± 0.014 0.396 ± 0.007 0.170± 0.030 >10 >10 >10 0.025 ± 0.012 >10 (3-53) Omi-30 0.085 ± 0.008 0.011± 0.002 >10 >10 0.008 ± 0.002 0.009 ± 0.001 0.343 ± 0.023 1.827 ±0.436 >10 Omi-31 0.014 ± 0.001 0.013 ± 0.002 >10 >10 0.014 ± 0.008 0.012± 0.001 >10 >10 >10 Omi-32 0.010 ± 0.006 2.682 ± 0.553 0.035 ± 0.016 >100.354 ± 0.064 >10 >10 >10 >10 Omi-33 0.027 ± 0.011 0.068 ± 0.022 0.013 ±0.004 >10 0.053 ± 0.006 >10 >10 > 10 Omi-34 0.007 ± 0.004 0.009 ±0.003 >10 >10 0.005 ± 0.000 0.005 ± 0.001 >10 >10 >10 Omi-35 0.018 ±0.004 0.094 ± 0.004 1.687 ± 0.441 >10 Omi-36 0.022 ± 0.004 0.030 ± 0.0140.024 ± 0.006 0.009 ± 0.001 >10 3.815 ± 0.054 >10 0.045 ± 0.005 >10(3-66) Omi-38 0.015 ± 0.004 0.005 ± 0.000 0.005 ± 0.001 >10 0.011 ±0.005 >10 >10 >10 >10 Omi-39 0.014 ± 0.002 0.026 ± 0.011 0.035 ±0.003 >10 0.027 ± 0.009 >10 >10 >10 >10Omi-41 >10 >10 >10 >10 >10 >10 >10 >10 0.0008 ± 0.001 Omi-42 0.033 ±0.004 0.021 ± 0.011 0.013 ± 0.001 0.010 ± 0.001 0.003 ± 0.000 0.011 ±0.005 0.028 ± 0.001 0.010 ± 0.001 0.008 ± 0.001 b Victoria BA.2 BA.4/5BA.2.75 BA.4.6 BA2.75.2 BA.2.3.20 BA.1 BA.4 + all AZD1063 0.052 ± 0.0550.003 ± 0.003 0.015 ± 0.054 0.021 ± 0.000 >10 >10 >10 >10 >10 AZD88950.001 ± 0.000 2.353 ± 0.317 >10 0.008 ± 0.000 >10 >10 0.007 ± 0.0015.114 ± 0.015 >10 AZD7442 0.001 ± 0.000 0.003 ± 0.001 0.065 ± 0.0070.017 ± 0.003 >10 >10 0.026 ± 0.001 2.735 ± 0.537 >10 REGN10987 0.002 ±0.001 0.616 ± 0.347 >10 >10 >10 >10 >10 >10 >10 REGN10933 0.001 ±0.002 >10 >10 >10 >10 >10 5.654 ± 0.019 >10 >10 ADG20 0.005 ±0.002 >10 >10 >10 >10 >10 >10 >10 >10 Ly-CoV555 0.022 ±0.000 >10 >10 >10 >10 >10 >10 >10 >10 Ly-CoV16 0.014 ±0.000 >10 >10 >10 >10 >10 >10 >10 >10 Ly-CoV1404 0.001 ± 0.000 0.001 ±0.000 0.001 ± 0.000 0.022 ± 0.000 0.001 ± 0.000 0.001 ± 0.001 0.013 ±0.005 >10 >10 5309 0.078 ± 0.027 0.558 ± 0.154 0.889 ± 0.041 0.202 ±0.041 1.029 ± 0.097 0.498 ± 0.538 0.977 ± 0.107 0.436 ± 0.010 0.582 ±0.072

Sequence Listing Amino Acid Sequence of Heavy Chain and Light ChainVariable Regions of Selected Antibodies

SEQ SEQ Antibody ID ID number: Amino acid sequence NO:Amino acid sequence NO: 2 EVQLVQSGAEVKKPGSSVK| 2 AIQLTQSPGTLSLPPGERATL 4VSCKASGGTFSNYAISWVR SCRASQSVSSSYLAWYQQK QAPGQGLEWMGGIIPIFGTAPGQAPRLLIYGASSRATGIP NYAQNFQGRVTITADESMS DRFSGSGSGTDFTLTISRLDTAYMELSSLRSEDTAVYYC PEDFAVYYCQQYGSSLTFG AGGGRYCSGGRCHSAYSAY GGTKVDIKWGQGTLVTVSS 22 QVQLVESGGGLVHPGGSLR 12 AIQLTQSPSSLSASVGDRVT 14LSCSASGFTFSNYAMHWVR ITCRASQSISSYLNWYQQEP QAPGKGLEYVSAISSSGDITYGKAPKLLIYAASSLQGGVP YADSVKGRFTISRDNSKNSL SRFSGSGSGTDFTLTISSLQPYLQMNSLRAEDTAVYYCV EDFATYYCQQSYTTPYTFG KDVTRTYYVVFDYWGQGT QGTKVDIKLVTVSS 40 QVQLVESGGGLVQPGGSLR 22 VIWMTQSPSSLSASVGDRV 24LSCAVSGFTVSRNYMSWVR TITCQASQDINNYLNWYQQ QAPGKGLEWVSLIYSGGSTFKPGKAPKLLIFDASNLETGV YADSVKGRFTISRDNSKNTL PSRFSGSGSGTDFTFTISSLQYLQMNSLRAEDTAVYYCA PEDIATYYCQQYDNLPAFG RDLFHRSGYHDYWGQGTL GGTKVDIK VTVSS44 EVQLVESGGGVVQPGRSLR 32 SYELTQPPSVSVSPGQTARI 34 LSCAASGFTFSNYGMHWVRTCSGDALPKKYAYWYQQK QAPGKGLEWVAVVWYDGS SGQAPVLVIYEDSKRPSGIPKKYYADSVKGRFTISRDNS ERFSGSSSGTMATLTISGAQ KNTLYLQMNSLRVEDTAVVEDEGDYYCYSRDSSGDH YYCARDFAVGEEIADSWGQ WVFGAGTKLTVL GTLVTVSS 45QVQLVESGGGVVQPGRSLR 42 DIQLTQSPSSLSASVGDRVTI 44 LSCAASGFTFSTYAMHWVRTCQASQDISNYLNWYQQKP QAPGKGLEWVAVLSYDGSN GKAPKLLIYDASNLETGVPSKYYADSVKGRFTISRDNSK RFSGGGSGTDFTFTITSLQPE NTLYLQMNSLRAEDTAVYDIATYYCQQYDNLPLTFGG YCAKGGSYAYYYYMDVW GTKVDIK GKGTTVTVSS 54VQLVQESGPGLVKPSETLSL 52 EIVMTQSPGTLSLSPGERATL 54 TCTVSGGSVSSGSYYWSWISCRASQSVSSSYLAWYQQKP RQPPGKGLEWIGYMYFSGS GQAPRLLIYGASSRATGIPDRTNYNPSLKSRVTISLATSKN FSGSGSGTDFTLTISRLEPED QFSLKLSSVTAADTAVYYCFAVYYCQHYGSSPVTFGQGT ARGDYDFWSGPPGRVDVW KVDIK GKGTTVTVSS 55QVQLVQSGPEVKKPGTSVK 62 DIQMTQSPGTLSLSPGERAT 64 VSCKASGFTFTSSAVQWVRLSCRASQSVSSSYLAWYQQK QARGQRLEWIGWIVVGSGN PGQAPRLLIYGASSRATGIPTNYAQKFQERVTITRDMST DRFSGSGSGTDFTLTISRLEP STAYMEMSSLRSEDTAVYYEDFGVYYCQQYGSSPWTFG CAAPACGTSCSDAFDIWGQG QGTKVEIK TMVTVSS 58QVQLVESGGGLVQPGRSL 72 SYELTQPPSVSVAPGQTARIT 74 RLSCAASGFTFDDYAMHWCGGNTIGSKSVHWYQQRPGQ VRQPPGKGLEWVSGVSWN APVLVVYDDSDRPSGIPERFSSGTIGYADSVKGRFIISRDN GSNSGNTATLTISRVEAGDE AKNSLYLQMNSLKAEDTAADYYCQVWDSSSDRVVFGG LYYCAREVGGTFGVLISRE GTKLTVL GGLDYWGQGTLVTVSS 61QVQLQESGPGLVKPSETLS 82 DIVMTQSPATLSVSPGERGT 84 LICTVSGGSVSSGNFYWSWLSCRASQSVSSNLAWYQQK IRQPPGKGLEWIGSIYYTG PGQAPRLLIYGASTRATGIPSPNYNPSLKSRVTISLDTS ARFSGSGSGTEFTLTISSLQS KNQFSLKLSSVTAADTAVYEDFAVYYCQQYNNWPPLT YCAREIYYYDRSGSYNSDA FGGGTKVDIK FDIWGQGTMVTVSS 75QVQLVESGGGVVQPGRSL 92 DIQLTQSPSSVSASVGDRVT 94 RLSCAASGFTFNNYPLHWITCRASQGISSWLAWYQQK VRQAPGKGPEWVAVISQD PGKAPKLLIYAVSSLQSGVPGGNKYYVDSVKGRFTISRD SRFSGSGSGTDFTLTISSLQP NSKNTLYLQMNNLRAEDTEDFATYYCQQAKSFPFTFG ALYYCARDVVVVVAARN PGTKVEIK HYYNGMDVWGQGTTVTV SS 88QLQLQESGPGLVKPSQTLSL 102 QSALTQPPSVSEAPRQRVTIS 104 TCTVSGGSISSGSYNWTWIRCSGSSSNIGNNAVNWYQQFP QPAGKGLEWIGRIYNSGSTN GKAPKLLIYYDDLLPSGVSDYNPSLKSRVTISVDTSKNQLS RFSGSKSGTSASLAISGVQSE LKVRSVTAADTAVYYCARDEADYYCAAWDDSLNVVVF HCSGGTCYPKYYYGMDVW GGGTKLTVL GQGTTVTVSS 111QVQLVESGPGLVKPSETLSL 112 VIWMTQSPSSLSASVGDRVTI 114 TCTVSGGSISSNSYFWGWIRTCRASQGIRNDLGWYQQKPG QPPGTGLEWIGNIYYTGSTY KAPKRLIYAASSLQSGVPSRFYNPSFESRVTMSVDTSKNQ SGSGSGTQFTLTISSLQPEDF FSLRLSSVTAADTAVYYCARATYYCLQINSYPLTFGGGTK HVRAYDYDAPFDIWGQGT VEIK MVTVSS 132QVQLQQWGAGLLKPSETL 122 QSVLTQEPSLTVSPGGTVTLT 124 SLTCAVYGGSFSGYYWSWCGSSTGAVTSGHYPYWFQQ IRQPPGKGLEWIGEINHSGS KPGQVPRTLIYDTRNKHSWTTNYNPSLKSRVTISVDTSK PARFSGSLLGGKAALTLSGA NQFSLKLSSVTAADTAVYQPEDEAEYYCLLSSSGARVF YCARTDYYDSIDWGQGTL GGGTKLTVL VTVSS 140EVQLVESGGGLVQPGGSLR 132 DIVMTQSPSSLSASVGDRITI 134 LSCAASGFTFSTYDIHWVRTCRASQSINNYLNWYQQKP QATGKGLEWVSAIGTAGDT GKAPKLLIYAASRLQTGVPSYYSGSVKGRFTISRENAKNS RFSGSGSGTDSTLTINTLQPE LYLQMNSLRAGDTAVYYCDFATYYCQQSYSAPPWTFG ARGSGTYFYYFDYWGQGT QGTKVDIK LVTVSS 148QVQLVESGPGLVKPSETLS 142 AIQMTQSPSSLSASVGDRV 144 LTCTVSGGSISSSYYWGWITITCRASQGISDYLAWFQQ RQPPGKGLEWIGSVYYSGS KPGKAPKSLIYAASSLQSGTYYNPSLKSRVTISVDTSK VPSKFSGGGSGTDFTLTISS NQFSLRLSSVTAADTAVYYLQPEDFATYYCQQYHSYPI CARLMTTEDYYSGMDVW TFGQGTRLEIK GQGTTVTVSS 150QVQLVESGGGLIQPGGSLR 152 EIVMTQSPSSLSASVGDRVT 154 LSCAASGVTVSSNYMSWVITCRASQGISSYLAWYQQK RQAPGKGLEWVSIIYSGGT PGKAPKLLIYAASTLQSGVPTYYADSVKGRFTISRDSSM SRFSGSGSGTDFTLTISSLQP NTLYLQMNSLRAEDTAVYEDFATYYCQQLDSYPPGYT YCARDLMVYGIDVWGQG FGQGTKVDIK TTVTVSS 158EVQLLESGGDLIQPGGSLRL 162 DIVMTQSPSFLSASVGDRV 164 SCAASGVTVSSNYMSWVRTITCRASQGISSYLAWYQQ QAPGKGLEWVSIIYPGGSTF KPGKAPKLLIQAASTLQSGYADSVKGRFTISRDNSKNTL VPSRFSGSGSGTEFTLTISSL YLQMHSLRAEDTAVYYCAQPEDFATYYCQQLNSYRYT RDLGSGDMDVWGKGTTVT FGQGTKVEIK VSS 159EVQLVESGGGVVQPGRSL 172 DIQLTQSPGTLSLSPGERAT 174 RLSCAASGFTFSSYGMHWLSCRASQSISGNYLAWYQH VRQAPGKGLEWVALISYD KPGQAPRLLIYGASTRATGIGGNRYYADSVKGRFTISRD PDRFSGSGSGTDFTLTISRLE NSKNTLYLQMNRLRAEDTPEDFAVYYCQQYGSSYTFG AMYYCAKDRDDGWDWY QGTKVEIK YFMDVWGKGTTVTVSS 165QVQLVQSGPEVKKPGTSV 182 DIVMTQSPGTLSLSPGERA 184 KVSCKASGFTFTSSAVQWTLSCRASQSVRSSYLAWYQ VRQARGQRLEWIGWIVVG QKPGQAPRLLIYGASRRGTSGNTNYAQKFQESVTITRD GIPDRFSGSGSGTDFTLTIS MSTSTAYMELSSLRSEDTARLEPEDFAVYYCQQYGSSP VYYCAAPHCIGGSCHDAF WTFGQGTKVEIK DIWGQGTMVTVSS 170QVQLVESGAEVKKPGESL 192 DIVMTQSPLSLSVTPGQPAS 194 KISCKGSGYSFTSYWIVWVISCKSSQSLLHSDGKTYLY RQMPGKGLEWMGIIYPGD WYLQKPGQPPQLLMYEVSSDTKYSPSFQGQVSISADK NRFSGVPDRFSGSGSGTDFT PISTAYLQWSRLKASDTALKISRVESEDVGVYYCMQS MYYCARLGNWLVDYWG IQLPRGITFGQGTRLEIK QGTLVTVSS 175EVQLVESGGGLIQPGGSLR 202 AIQMTQSPSSLSASVGDRVT 204 LSCAASGLTVSRNYMSWVITCQASQDISNFLNWYQQK RQAPGKGLEWVSLIYSGGS PGKAPKLLIYDASNLETGVPTYYADSVKGRFTISRDNSK SRFSGSGSGTDFTFTISSLQP NTLYLQMNSLRAEDTAVYEDIATYYCHQYDNLPRTFGQ YCARDLRGEVWGQGTMV GTKVDIK TVSS 177EVQLVESGGGLVQPGGSL 212 AIRMTQSPSSLSASVGDRV 214 RLSCAASGFTFSNYDMHWTITCRASQSISSYLNWYQQ VRQATGKGLEWVSLIGTA KPGKAPKLLIFAASSLQSGVGDTYYPDSVKGRFTISREN PSRFSGSGSGTDSTLTISSL AKNSLYLQMNSLRAGDTAQPEDFATYYCQQSYSNPPE VYYCARGQHTQIGHYYYY GSFGQGTKVEIK YMDVWGKGTTVTVSS 181EVQLVETGGGLIQPGGSLRL 222 QSVLTQPASMSGSPGQSITI 224 SCAASGFTVSSNYMSWVRQSCTGTSSDVGGYNLVSWYQ APGKGLEWVSVVYGGGTT QHPGKAPKLMIYEGSKRPSGYYADSVKGRFTISRDNSKN VSNRFSGSKSGNTASLTISG TLYLQMNSLRAEDTAVYYCLQAEDEADYYCCSYAGSSN ATDNGYSYGFSFDYWGQG WVFGGGTKLTVL TLVIVSS 182QVQLVESGAEVEKPGASV 232 QSVLTQPASVSGSPGQSITI 234 KVSCKASGYTFTGYYMHSCTGTSSDVGSYNLVSWYQQ WVRQAPGQGLEWMGWIN HPGKAPKLMIYEGSKRPSGPISGGTNYAQKFQGRVTM VSNRFSGSKSGNTASLTISG TRDTSISTAYMDLSRLRSDLQAEDEADYYCCSYAGSST DTAVYYCARGTYYYDSSG LVFGGGTKLTVL YIPFDYWGQGTLVTVSS183 QVQLVQSGSELKKPGASV 242 SYELTQPLSVSVALGQTASI 244 KVSCKASGYTFSSYAMTWTCGGNNIGSKNVHWYQQK VRQAPGQGLEWMGWINT PGQAPVLVIYRDSNRPSGIPNTGNPTYAQGFTGRFVFSL ERFSGSNSGNTATLTISRAQ DTSVSTAYLQISSLKAEDTAGDEADYNCQVWDSSVVF AVYYCARALGYCSSTSCYP GGGTKLTVL AWAAFDIWGQGTMVTVSS 222EVQLVESGGGLIQPGGSLR 252 DVVMTQSPGTLSLSPGERA 254 LSCAASGLTVSSNYMSWVTLSCRASQSVPSSYLAWYQQ RQAPGKGLEWVSVIYSGGS KPGQAPRLLIYGASTRATGITFYADSVKGRFTISRDNSK PDRFSGSGSGTDFTLTISRL NTLYLQMNSLGAEDTAVYEPEDFAVYYCQHYDTSPRFG YCARGEGSPGNWFDPWGQ GGTKVDIK GTLVTVSS 253QVQLVQSGPEVKKPGTSV 262 DIQMTQSPGTLSLSPGEGATL 264 KVSCKASGFTFTTSAVQWSCRASQSVSSSYLAWYQQKP VRQARGQRLEWIGWIVVG GQAPRLLIYGASSGATGIPDRSQNTNYAQKFQERVTITRD FSGSGSGTDFTLTISRLEPE MSTTTAYMELSSLRSEDTADFAVYYCQQYGSSPYTFGQGT VYFCAAPHCNSTSCYDAFD KVEIK IWGQGTMVTVSS 269QVQLVESGGGLIQPGGSLRL 272 AIQLTQSPSFLSASIGDRVTI 274 SCAASGLTVNRNYMSWIRQTCRASQGISSYLAWYQQKP APGKGLEWVSVIYSGGSTF GKAPKLLIYAASTLQSGVPSYADSVKGRFTISRDNSKNTL RFSGSGSGTEFTLTISSLQPE SLQMNSLRAEDTAIYYCARDFASYYCQQLNSYPAPVFG DFYEGSFDIWGQGTMVTVS PGTKVDIK S 278QVQLVQSGAEVKKPGASV 282 DIQMTQSPSSLSASVGDRLTI 284 KVSCKASGYIFIRYGISWVTCRASQSIASYLNWYQQKPG RQAPGQGLEWMGWISAN KAPKLLIYAASSLQSGVPSRFNGYTNYAQKLQGRVTMTT SGSGSGTDFTLTISSLQPEDF DTSTSTAYMELRSLRSDDTATYHCQQSYSTLGITFGPGT AVYYCARDGGILTGYLDY KVDIK FDHWGQGTLVTVSS 281QVQLVESGGGLVQPGGSL 292 DIVMTQTPLSSPVTLGQPAS 294 RLSCAASGFPFSIYWMSWVISCRSSQSLVHRDGNTYLS RQAPGKGLEWVANIKQDG WLQQRPGQPPRLLIYKISNRSEKYYVDSVKGRFTISRDN FSGVPDRFSGSGAGTDFTL AKNSLYLHMNSLRGEDTAKISRVEAEDVGVYYCMQA VYYCASRYYDFRPEAWFD TQFPHGYTFGQGTKVEIK YWGQGTLVTVSS282 QVQLQESGGGLVQPGGSLR 302 EIVLTQSPGTLSLSPGEKVT 304 LSCSASGFTVSSNYMTWVRLSCRASQSVSSTYLAWYQQ QAPGKGLEWVSVIYSGGST KPGQAPRLLIYGASSRATGFYADSVKGRFTISRDNSKNT VPDRFRGSGSGTDFTLTISR LYLQMNSLRAEDTAVYYCLEPEDFAVYYCQQYGSSLY ARDLEEAGGFDYWGQGTL TFGQGTKVDIK VTVSS 285QLQLQESGPGLVKPSETLS 312 DIQMTQSPSSLSASVGDRV 314 LTCTVSGDSVSNYYWSWITITCRASQSISSYLNWYQQK RQPAGKGLEWIGRIYTSGS PGKAPKLLIYAASSLQSGVPTNYNPSLKSRVTMSVDTS SRFSGSGSGTDFTLTINSLQ KNQFSLKLSSVTAADTAVPEDFATYYCQQSYSTPALT YYCARDHRASRYSSGWY FGGGTKVDIK EWWNCFDPWGQGTLVTV SS316 QVQLVQSGAEVKKPGASV 322 QAVLTQPPSASGSPGQSVTI 324 KVSCKASGYTFTGYYMHSCTGTSSDVGGYNYVSWYQ WVRQAPGQGLEWMGWIN QHPGKAPKLMIYEVSKRPSPNSGGTNYTQKFQGRVTM GVPDRFSGSKSGNTASLTV TRDTSISTAYMELSRLRSSGLQAEDEADYYCSSYAGS DDTAVYSCARDMAFSMVR NHWVFGGGTKLTVL GSFDYWGQGTLVTVSS318 QVQLVQSGPEVKKPGTSV 332 AIRMTQSPGTLSLSPGERAT 334 KVSCKASGFTLTSSAMQWLSCRASQSVSSSYLAWYQQR VRQARGQRLEWIGWIVVG PGQAPRLLIYGTSSRATGIPSQNTNYAQKFQERVTITRD DRFSGSGSGTDFTLTISRLEP MSTSTAYMELSSLRSEDTAEDFAVYYCQQYGYSVYTFG VYYCAAGRGYNSDFDYWG QGTKVDIK QGTLVTVSS 334QVQLVESEAEVKKPGASV 342 EIVMTQSPATLSLSPGERAT 344 KVSCKASGYTFTSYYMHWLSCRASQSVSSYLAWYQQK VRQAPGQGLQWMGIINPS PGQAPRLLIYDASNRATGIPAGSTSYAQKFQGRVTMTT ARFSGSGSGTDFTLTISSLEP DTSTTTVYMELSSLRSEDTEDFAVYYCQQRRNWLFTFG AVYYCARDSVLVPAANAF PGTKVDIK DIWGQGTMVTVSS 361QVQLVQSGAEVKKPGAS 352 AIRMTQSPSTLSASVGDRVT 354 VKVSCKASGDTFTSYTLHITCRASQSISGWLAWYQQK WVRQAPGQRLEWMGWI PEKAPKLLIYDASNLESGVPNAGNGYTKYSQKFQGRV SRFSGSGSGTEFTLTINSLQP TITRDTSASTAYMELSSLRDDFATYYCQQYNSYPWTF SEDTAVYYCAKCTMIVDY GQGTKVDIK FDYWGQGTLVTVSS 382EVQLVQSGAEVKKPGASV 362 QPVLTQPPSVSVAPGKTARI 364 KVSCKASGYTFTSYDINWTCGGSNIGSKSVHWYQQKP VRQATGQGLEWMGWMN GQAPVLIIYYDSDRPSGIPERPHSDTTGYAQKFQGRVTM FSGSNSGNTATLTISRVEAG TRNTSITTAYMELSSLRSEDDEADFYCQVWDSSTDHVV TAVYYCAQGPIAVNYMD FGGGTKLTVL VWGKGTTVTVSS 384EVQLVESGGGLVKPGESL 372 DIQLTQSPSSLSASVGDRVT 374 RLSCAASGFTFSDYYMTWITCRASQGISNYLAWYQQK IRQAPGKGLEWVSYIRSSG PGKVPKLLIYAASTLQSGVPHTIYYADSVKGRFTISRDN SRFSGSGSGTDFTLTISSLQP AKNSLYLQMNSLRVEDTAEDVATYYCQKYNNALGTF VYYCARGGVLRFLEWPLN GQGTKVEIK AFDIWGQGTMVTVSS 394EVQLVQSGAEVKKPGASV 382 QSVVTQPASVSGSPGQSITIS 384 KVSCKASGYTFTGYYMHCTGTSSDVGGYNFVSWYQ WVRQAPGQGLEWMGWIS QHPGKAPKLMIYEVSNRPSPNSGGTNYAQKFQGRVTM GVSNRFSGSKSGITASLTISG TRDTSITTAYMDLSRLRSDDLQAEDEADYYCNSYTSNST TAVYYCARGYYYEALDAF RVFGGGTKLTVL DIWGQGTMVTVSS 398QVQLVESGGGLVQPGGSLR 392 QTVLTQPASVSGSPGQSITIS 394 LSCAASGFTVSSNYMTWVRCTGTSSDVGGYNYVSWYQ QAPGKGLEWVSVIYSGGSTY QHPGKAPKLMIYEVTKRPSGYADSVKGRFTISRDNSKNTL VPDRFSGSKSGNTASLTVS YLQMNSLRADDTAVYYCAGLQAEDEADYYCSSYAGS RDSTADYDFWSGYYVGAF NNWVFGGGTKLTVL HIWGQGTMVTVSS

Nucleotide Sequence of Heavy Chain and Light Chain Variable Regions ofSelected Antibodies

Heavy chain Light chain SEQ SEQ Antibody ID ID number:Nucleotide Sequence NO: Nucleotide sequence NO: 2gaggtgcagctggtgcagtctggggctga 1 gccatccagttgacccagtctccaggcaccct 3ggtgaagaagcctgggtcctcggtgaagg gtctttgcctccaggggaaagagccaccctcttctcctgcaaggcttctggaggcaccttcag cctgcagggccagtcagagtgttagcagcagcaactatgctatcagctgggtgcgacaggc ctacttagcctggtaccagcagaaacctggccccctggacaagggcttgagtggatgggag aggctcccaggctcctcatctatggtgcatccaggatcatccctatctttggtacagcaaactac gcagggccactggcatcccagacaggttcaggcacagaacttccagggcagagtcacgatt tggcagtgggtctgggacagacttcactctcaaccgcggacgaatccatgagcacagccta ccatcagcagactggaccctgaagattttgcacatggagctgagcagcctgagatctgagg gtgtattactgtcagcaatatggtagctcactcaacacggccgtatattactgtgcgggaggtg ctttcggcggagggaccaaagtggatatcaaaggaggtattgtagtggtggtaggtgccactc c tgcctactctgcctactggggccagggaaccctggtcaccgtctcctcag 22 caggtgcagctggtggagtctgggggagg 11gccatccagttgacccagtctccatcctccctg 13 cttggtccaccctggggggtccctgagacttctgcatctgtgggagacagagtcaccatcact ctcctgttcagcctctggattcaccttcagtatgccgggcaagtcagagcattagcagttattta actatgctatgcactgggtccgccaggctcaattggtatcagcaggaaccagggaaagccc cagggaagggactggaatatgtttcagctactaaactcctgatctatgctgcatccagtttgca ttagtagtagtggggatatcacatactacgcaggtggggtcccatcaaggttcagtggcagtg ggactccgtaaagggcagattcaccatctcgatctgggacagatttcactctcaccatcagca cagagacaattccaagaactcactgtatcttgtctgcaacctgaagattttgcaacttactactg caaatgaacagtctgagagctgaggacactcaacagagttacactaccccgtacacttttgg ggctgtttattactgtgtgaaagatgtaacgaccaggggaccaaagtggatatcaaac ggacctactacgtagtctttgactactggggccagggaaccctggtcaccgtctcctcag 40 caggtgcagctggtggagtctgggggagg 21gtcatctggatgacccagtctccatcctccctgt 23 cttggtccagcctggggggtccctgagactctgcatctgtaggagacagagtcaccatcactt ctcctgtgcagtctctggattcaccgtcagtagccaggcgagtcaggacattaacaactatttaa ggaactacatgagctgggtccgccaggctattggtatcagcagaaaccagggaaagcccct ccagggaaggggctggagtgggtctcactaagctcctgatcttcgatgcctccaatttggaaa tatttatagcggtggtagcacattctacgcacaggggtcccatcaaggttcagtggcagtgg gactccgtgaagggcagattcaccatctccatctgggacagattttactttcaccatcagcagc agagacaattccaagaacacgctgtatcttcctacagcctgaagatattgcaacatattactgtc aaatgaacagcctgagagccgaggacacaacagtatgataatctccctgccttcggcggag ggctgtgtattactgtgcgagagatctgtttcggaccaaagtggatatcaaac ataggagtggttatcacgactactggggccagggaaccctggtcaccgtctcctcag 44 gaagtgcagctggtggagtctgggggagg 31tcctatgagctgactcagccaccctcggtgtca 33 cgtggtccagcctgggaggtccctgagactgtgtccccaggacaaacggccaggatcacctgc ctcctgtgcagcgtctggattcaccttcagtatctggagatgcattgccaaaaaaatatgcttattg actatggcatgcactgggtccgccaggctcgtaccagcagaagtcaggccaggcccctgta caggcaaggggctggagtgggtggcggttctggtcatctatgaggacagcaaacgaccctc gtatggtatgatggaagcaagaaatactatgcgggatccctgagagattctctgggtccagctc cagactccgtgaagggccgattcaccatctagggacaatggccaccttgactatcagtgggg ccagagacaattccaagaacaccctgtatctcccaggtggaggatgaaggtgactactactgt gcaaatgaacagcctgagagtcgaggacatactcaagagacagcagtggtgatcattgggt cggctgtgtattactgcgcgagagattttgcgttcggcgcagggaccaagctgaccgtccta ggtgggggaggagatcgctgactcctggg ggccagggaaccctggtcaccgtctcctcag 45 caggtgcagctggtggagtctgggggag 41gacatccagttgacccagtctccatcctccctg 43 gcgtggtccagcctgggaggtccctgagtctgcatctgtaggagacagagtcaccatcact actctcctgtgcagcctctggattcaccttctgccaggcgagtcaggacattagcaactattta agtacctatgctatgcactgggtccgccaaattggtatcagcagaaaccagggaaagcccct ggctccaggcaaggggctggagtgggtaagctcctgatctacgatgcatccaatttggaa ggctgttctttcatatgatggaagcaataaaacaggggtcccatcaaggttcagtggaggtg tactacgcagactccgtgaagggccgattgatctgggacagattttactttcaccatcaccag caccatctccagagacaattccaagaacacctgcagcctgaagatattgcaacatattactgt cgctgtatctgcaaatgaacagcctgagacaacagtatgataatctcccgctcactttcggcg gctgaggacacggctgtgtattactgtgcgagggaccaaagtggatatcaaac gaaagggggctcgtacgcgtactactactacatggacgtctggggcaaagggaccac ggtcaccgtctcctca 54gttcagctggtgcaggagtcgggcccagg 51 gaaatagtgatgacgcagtctccaggcaccct 53actggtgaagccttcggagaccctgtccct gtctttgtctccaggggaaagagccaccctctccacctgcactgtctctggtggctccgtcagt ctgcagggccagtcagagtgttagcagcagctaagtggtagttactactggagctggatccgg cttagcctggtaccagcagaaacctggccaggcagcccccagggaagggactggagtgga ctcccaggctcctcatctatggtgcatccagcagttgggtatatgtatttcagtgggagcaccaa ggccactggcatcccagacaggttcagtggcctataatccctccctcaagagtcgagtcacc agtgggtctgggacagacttcactctcaccatcatatcattagccacgtccaagaaccagttct agcagactggagcctgaagattttgcagtgtatccctgaagctgagctctgtgaccgctgcgga tactgtcagcactatggtagttcacccgtaacttcacggccgtctattactgtgcgagaggggat ttggccaggggaccaaagtggatatcaaactacgatttttggagtggtccccccggtcggg tggacgtctggggcaaagggaccacggtcaccgtctcctcag 55 caggtgcagctggtgcagtctgggcctga 61gacatccagatgacccagtctccaggcaccct 63 ggtgaagaagcctgggacctcagtgaagggtctttgtctccaggggaaagagccaccctctc tctcctgcaaggcttctggattcacctttactctgcagggccagtcagagtgttagcagcagcta agctctgctgtgcagtgggtgcgacaggcttagcctggtaccagcagaaacctggccagg ctcgtggacaacgccttgagtggataggactcccaggctcctcatctatggtgcatccagca tggatcgtcgttggcagtggtaacacaaagggccactggcatcccagacaggttcagtgg ctacgcacagaagttccaggaaagagtcacagtgggtctgggacagacttcactctcaccat ccattaccagggacatgtccacaagcacacagcagactggagcctgaagattttggagtgt gcctacatggagatgagcagcctgagatattactgtcagcagtatggtagctcaccgtgga ccgaggacacggccgtgtattactgtgcgcgttcggccaagggaccaaggtggaaatcaa gcaccggcctgtggtaccagctgctctga actgcctttgatatctggggccaagggacaat ggtcaccgtctcttcag 58caggtgcagctggtggagtctgggggag 71 tcctatgagctgacacagccaccctcggtgtca 13gcttggtacagcctggcaggtccctgaga gtggccccaggacagacggccagaattacctgtctctcctgtgcagcctctggattcacctttgat gggggaaacaccattggaagtaaaagtgtgcgattatgccatgcactgggtccggcaacc actggtaccagcagagaccaggccaggccctccagggaagggcctggagtgggtctca ctgtgctggtcgtctatgatgatagcgaccggcggtgtcagttggaacagtggtaccatagg cctcagggatccctgagcgattctctggctccactatgcggactctgtgaagggccgattcat actctgggaacacggccaccctgaccatcagcatctccagagacaacgccaagaactcc cagggtcgaagccggggatgaggccgactatctgtatctgcaaatgaacagtctgaaagct tactgtcaggtgtgggatagtagtagtgatcgggaggacacggccttgtattactgtgcaag gtggtattcggcggagggaccaagctgaccgagaagtgggggggacttttggagtccttat tcctag ttcacgcgaggggggacttgattactggggccagggaaccctggtcaccgtctcctca g 61 caggtgcagctgcaggagtcgggccca 81gatatcgtgatgactcagtctccagccaccctg 83 ggactggtgaagccttcggagaccctgtctctgtgtctccaggggaaagaggcaccctctc cctcatctgcactgtctctggtggctccgtcctgcagggccagtcagagtgttagcagcaactt agcagtggtaatttctactggagctggatcagcctggtaccagcagaaaccgggccaggct cggcagcccccagggaagggactggagcccaggctcctcatctatggtgcatccacgag tggattggatctatctattacactgggagccggccactggtatcccagccaggttcagtggca ccaactacaacccctccctcaagagtcgagtgggtctgggacagagttcactctcaccatca gtcaccatatccctagacacgtccaagaagcagcctgcagtctgaagattttgcagtttatta ccagttctccctgaagctgagctctgtgacctgccagcagtataataactggcctccgctcac cgctgcggacacggccgtgtattactgtgtttcggcggagggaccaaagtggatatcaaac cgagagagatctattattatgatagaagtggttcttacaactctgatgcttttgatatctggg gccaagggacaatggtcaccgtctcttca g 75caggtgcagctggtggagtctgggggag 91 gacatccagttgacccagtctccatcttccgtgt 93gcgtggttcagcctgggaggtccctgag ctgcatctgtaggagacagagtcaccatcacttactctcctgtgcagcctctggattcaccttc gtcgggcgagtcagggtattagcagctggttaaataactatcctttgcactgggtccgccag gcctggtatcagcagaaaccagggaaagcccgctccaggcaaggggccggagtgggtg ctaagctcctgatctatgctgtatccagtttgcagcagttatttcacaggatggaggcaataa aagtggggtcccatcaaggttcagcggcagtgatactacgtagactccgtgaagggccgatt gatctgggacagatttcactctcaccatcagcacaccatctccagagacaattccaagaaca gcctgcagcctgaagattttgcaacttactattgccctgtatctgcaaatgaacaacctgaga tcaacaggctaagagtttccctttcactttcggcgctgaggacacggctctgtattactgtgc cctgggaccaaggtggagattaaacgagagatgttgtagtggtggtagctgcta ggaaccactactacaacggtatggacgtctggggccaagggaccacggtcaccgtct cctca 88 cagctgcagctgcaggagtcgggccca 101caatctgccctgactcagccaccctcggtgtct 103 ggactggtgaagccttcacagaccctgtcgaagcccccaggcagagggtcaccatctcct cctcacctgcactgtctctggtggctccatgttctggaagcagctccaacatcggaaataat cagtagtggtagttataattggacctggatgctgtaaactggtaccagcagttcccaggaaa ccggcagcccgccgggaagggactggaggctcccaaactcctcatctattatgatgatctg gtggattgggcgtatatataatagtgggagctgccctcaggggtctctgaccgattctctggc caccaactacaacccctccctcaagagtctccaagtctggcacctcagcctccctggccatc gagtcaccatatcagtagacacgtccaagaagtggggtccagtctgaggatgaggctgattat accagttgtccctgaaggtgaggtctgtgatactgtgcagcatgggatgacagcctgaatgt ccgccgcagacacggccgtgtattactgtgcgtggtattcggcggagggaccaagctgacc cgagacattgcagtggtggtacctgctac gtcctagccgaagtactactacggtatggacgtctg gggccaagggaccacggtcaccgtctcc tca 111caggtgcagctggtggagtcgggcccag 111 gtcatctggatgacccagtctccatcctccctgt 113gactggtgaagccttcggagaccctgtcc ctgcatctgtaggagacagagtcaccatcacttctcacctgcactgtctctggtggctccatc gccgggcaagtcagggcattagaaatgatttaagcagtaatagttacttctggggctggatc ggctggtatcagcagaaaccagggaaagcccgccagcccccagggacggggctggag cctaagcgcctgatctatgctgcatccagtttgtggattgggaatatctattatactgggagca caaagtggggtcccatcaaggttcagcggcacctactacaacccgtcgttcgagagtcga gtggatctgggacacaattcactctcacaatcagtcaccatgtccgtagacacgtcgaagaa gcagcctgcagcctgaagattttgcaacttattccagttctccctgaggctgagctctgtgac actgtctacagattaatagttatccgctcactttccgccgcagacacggctgtgtattactgtg ggcggagggaccaaggtggaaatcaaaccgagacatgtcagggcctacgactatgat gccccttttgatatctggggccaagggacaatggtcaccgtctcttcag 132 caggtacagctgcagcagtggggcgca 121cagtctgtgctgactcaggagccctcactgact 123 ggactgttgaagccttcggagaccctgtcgtgtccccaggagggacagtcactctcacctg cctcacctgcgctgtctatggtgggtccttctggctccagcactggagctgtcaccagtggtc agtggttactactggagctggatccgccagattatccctactggttccagcagaagcctggcc cccccagggaaggggctggagtggattgaagtccccaggacactgatttatgatacaagg gggaaatcaatcatagtggaagcaccaaaacaaacactcctggacccctgcccggttctc ctacaacccgtccctcaagagtcgagtcaaggctccctccttgggggcaaagctgccctgac ccatatcagtagacacgtccaagaaccagcctttcgggtgcgcagcctgaggatgaggctg ttctccctgaagctgagttctgtgaccgccaatattactgcttgctctcctctagtggtgctcgg gcggacacggctgtgtattactgtgcgaggtgttcggcggagggaccaagctgaccgtcc aactgattactatgatagtatagactgggg tagccagggaaccctggtcaccgtctcctcag 140 gaggtgcagctggtggagtctgggggag 131gacatcgtgatgactcagtctccatcctccctgt 133 gcttggtacagcctggggggtccctgagacctgcatctgtaggagacagaatcaccatcactt tctcctgtgcagcctctggattcaccttcagtagccgggcaagtcagagcattaacaactattta cctacgacatccactgggtccgccaagctaaattggtatcagcagaaaccagggaaagccc caggaaaaggtctggagtgggtctcagctatctaagctcctgatctatgctgcatcccgtttgca tggtactgctggtgacacatactattcaggctaactggggtcccatcaaggttcagtggcagtg ccgtgaagggccgattcaccatctccagaggatctgggacagattccactctcaccatcaaca aaaatgccaagaactccttgtatcttcaaatgctctgcaacctgaagattttgcaacttactactg aacagcctgagagccggggacacggctgtcaacagagttacagtgcccctccgtggacgtt tgtattactgtgcaaggggtagtgggacctacggccaagggaccaaagtggatatcaaac cttctactactttgactactggggccagggaaccctggtcaccgtctcctcag 148 caggtgcagctggtggagtcgggcccag 141gccatccagatgacccagtctccatcctcactg 143 gactggtgaagccttcggagaccctgtccctctgcatctgtaggagacagagtcaccatcact tcacctgcactgtctctggtggctcgatcagtgtcgggcgagtcagggcattagcgattattta cagttcttactactggggctggatccgccaggcctggtttcagcagaaaccagggaaagcccc cccccagggaaggggctggagtggattgtaagtccctgatctatgctgcatccagtttgcaaa ggagtgtctattatagtgggagcacctactagtggggtcccatcaaagttcagcggcggtgga caacccgtccctcaagagtcgagtcaccattctgggacagatttcactctcaccatcagcagc atccgtggacacgtccaagaaccagttctccctgcagcctgaagattttgcaacttattactgcc ctgaggctgagctctgtgaccgccgcagaaacagtatcatagttacccgatcaccttcggcc cacggctgtgtattattgtgcgaggctgatgaagggacacgactggagattaaac accacggaagactactactccggtatggacgtctggggccaagggaccacggtcaccgt ctcctca 150 caggtgcagctggtggagtctggaggagg151 gaaatagtgatgacgcagtctccatcctccctg 153 cttgatccagcctggggggtccctgagacttctgcatctgtaggagacagagtcaccatcact ctcctgtgcagcctctggggtcaccgtcagttgccgggccagtcagggcattagcagttattta agcaactacatgagttgggtccgccaggctgcctggtatcagcaaaaaccagggaaagccc ccagggaaggggctggagtgggtctcaatctaagctcctgatctatgctgcatccactttgca tatttatagtggtggtaccacatactacgcagaagtggggtcccatcaaggttcagcggcagtg actccgtgaagggccgattcaccatctccagatctgggacagatttcactctcaccatcagca gagactcttccatgaacacgctgtatcttcaagcctgcagcctgaagattttgcaacttattactg atgaacagcctgagagccgaggacacggtcaacagcttgatagttacccccccgggtacac ccgtgtattactgtgcgagagatctgatggtttttggccaggggaccaaagtggatatcaaac gtacggtatagacgtctggggccaagggaccacggtcaccgtctcctca 158 gaggtgcagctgttggagtctggaggag 161gacatcgtgatgactcagtctccatccttcctgtct 163 acttgatccagcctggggggtccctgagagcatctgtaggagacagagtcaccatcacttgcc ctctcctgtgcagcctctggggtcaccgtcgggccagtcagggcattagcagttatttagcctg agtagcaactacatgagctgggtccgccaggtatcagcaaaaaccggggaaagcccctaagct gctccagggaaggggctggagtgggtctcctgatccaagctgcatccactttgcaaagtggg caattatttatcccggtgggagcacattctagtcccatcaaggttcagcggcagtggatctggg cgcagactccgtgaagggccgattcaccacagaattcactctcacaatcagcagcctgcagcc atctccagagacaattccaagaacacgctgttgaagattttgcaacttattactgtcaacagcttaata atcttcaaatgcacagcctgagagccgaggttaccggtacacttttggccaggggaccaagg gacacggccgtgtattactgtgcgagagatggagatcaaac tcttggctcaggggacatggacgtctggg gcaaagggaccacggtcaccgtctcctca159 gaggtgcagctggtggagtctgggggag 171 gacatccagttgacccagtctccaggcaccct173 gcgtggtccagcctgggaggtccctgag gtctttgtctccaggggaaagagccaccctctcactctcctgtgcagcctctggattcaccttc ctgcagggccagtcagagtattagcggcaactagtagctatggcatgcactgggtccgcca acttagcctggtaccagcataaacctggccagggctccaggcaaggggctggagtgggtg gctcccagactcctcatctatggtgcatccaccgcacttatatcatatgatggaggtaatagat agggccactggcatcccagacaggttcagtgactatgcagactccgtgaagggccgattc gcagtgggtctgggacagacttcactctcaccaccatctccagagacaattccaagaacac atcagcagactggagcctgaagattttgcagtgctgtatctgcaaatgaacagactgagag gtattactgtcagcagtatggtagctcgtacactctgaagacacggctatgtattactgtgcga tttggccaggggaccaaggtggagatcaaacaagatcgtgatgatgggtgggattggtact acttcatggacgtctggggcaaagggaccacggtcaccgtctcctca 165 caggttcagctggtgcagtctgggcctga 181gatatcgtgatgacccagtctccaggcaccct 183 ggtgaagaagcctgggacctcagtgaagatctttgtctccaggggaaagagccaccctctc gtctcctgcaaggcttctggattcacctttactgcagggccagtcagagtgttagaagcagcta ctagctctgctgtgcagtgggtgcgacagcttagcctggtaccagcagaaacctggccagg gctcgtggacagcgccttgagtggataggctcccaggctcctcatctatggtgcatccaggag atggatcgtcgttggcagtggtaacacaagggcactggcatcccagacaggttcagtggca actacgcacagaagttccaggaaagcgtcgtgggtctgggacagacttcactctcaccatca accattaccagggacatgtccacaagcacgcagactggagcctgaagattttgcagtgtatt agcctacatggagctgagcagcctgagatactgtcagcagtatggtagctcaccctggacgt ccgaggacacggccgtgtattactgtgcgtcggccaagggaccaaggtggaaatcaaac gccccacattgtattggtggtagctgccatgatgcttttgatatctggggccaagggacaat ggtcaccgtctcttcag 170caggtgcagctggtggagtcaggagcag 191 gatattgtgatgactcagtctcctctctctctgtc 193aggtgaaaaagcccggggagtctctgaa cgtcacccctggacagccggcctccatctcctgatctcctgtaagggttctggatacagcttt gcaagtctagtcagagcctcctgcatagtgatgaccagctactggatcgtctgggtgcgcca gaaagacctatttgtattggtacctgcagaagcgatgcccgggaaaggcctggagtggatg caggccagcctccacagctcctgatgtatgaagggatcatctatcctggtgactctgatacc gtttccaaccggttctctggagtgccagataggaaatacagtccgtccttccaaggccaggt ttcagtggcagcgggtcagggacagacttcaccagcatctcagccgacaagcccatcagca acttaaaatcagccgggtggagtctgaggatgccgcctacctgcagtggagcaggctgaa ttggggtttattactgcatgcaaagtatacagcttggcctcggacaccgccatgtattactgtg cctcgcgggatcaccttcggccaagggacaccgagactagggaattggctggtggactac gactggagattaaactggggccagggaaccctggtcaccgtct cctcag 175 gaggtgcagctggtggagtctggaggag 201gccatccagatgacccagtctccatcctccctgt 203 gcttgatccagcctggggggtccctgagactgcatctgtaggagacagagtcaccatcacttg ctctcctgtgcagcctctgggctcaccgtcccaggcgagtcaggacattagcaactttttaaatt agtcgcaattacatgagctgggtccgccaggtatcagcagaaaccagggaaagcccctaag ggctccagggaaggggctggagtgggtctcctgatctacgatgcatccaatttggaaacag ctcacttatttatagcggtggtagcacatacgggtcccatcaaggttcagtggaagtggatctg tacgcagactccgtgaagggccgattcacggacagattttactttcaccatcagtagcctgcag catctccagagacaattccaagaacacgccctgaagatattgcaacatattactgtcaccagta tgtatcttcaaatgaacagcctgagagccgtgataatctccctcgaacgttcggccaagggac aggacacggccgtgtattactgtgcgagagcaaagtggatatcaaac atctacgcggagaagtctggggccaaggg acaatggtcaccgtctcttcag177 gaggtgcagctggtggagtctgggggag 211 gccatccggatgacccagtctccatcgtccct213 gcttggtacagcctggggggtccctgaga gtctgcatctgtaggagacagagtcaccatcactctcctgtgcagcctctggattcaccttca cttgccgggcaagtcagagcattagcagctattgtaactacgacatgcactgggtccgccaa taaattggtatcagcagaaaccagggaaagccgctacaggaaaaggtctggagtgggtctca cctaagctcctgatctttgctgcatccagtttgccttattggtactgctggtgacacatactatc aaagtggggtcccatcaaggttcagtggcagtcagactccgtgaagggccgattcaccatc ggatctgggacagattccactctaaccatcagtccagagaaaatgccaagaactccttgtat cagtctgcaacctgaagattttgcaacttactaccttcaaatgaacagcctgagagccgggg tgtcaacagagttacagtaaccctccggagggacacggctgtgtattactgtgcaagaggg cagttttggccaggggaccaaagtggagattacaacacactcaaatcggtcactactactac aac tactacatggacgtctggggcaaagggaccacggtcaccgtctcctca 181 gaagtgcagctggtggagactggaggag 221cagtctgtgctgactcagcctgcctccatgtctg 223 gcttgatccagcctggggggtccctgagaggtctcctggacagtcgatcaccatctcctgca ctctcctgtgcagcctctgggttcaccgtcctggaaccagcagtgatgttgggggttataac agtagcaactacatgagctgggtccgccacttgtctcctggtaccaacagcacccaggcaa ggctccagggaaggggctggagtgggtagcccccaaactcatgatttatgagggcagtaa ctcagttgtttatggcggtggtaccacatacgcggccctcaggggtttctaatcgcttctctgg tacgcagactccgtgaagggccgattcacctccaagtctggcaacacggcctccctgacaa catctccagagacaattccaagaacacgctctctgggctccaggctgaggacgaggctgat tgtatcttcaaatgaacagcctgagagccgtattactgctgctcatatgcaggtagtagtaattg aggacacggccgtatattactgtgcgactggtgttcggcggagggaccaagctgaccgtc gacaatggatacagctatggtttttcatttg ctagactactggggccagggaaccctggtcatc gtctcctcag 182caggtgcagctggtggagtctggggctg 231 cagtctgtgctgactcagcctgcctccgtatctg 233aggtggagaagcctggggcctcagtgaa ggtctcctggacagtcgatcaccatctcctgcacggtctcctgcaaggcttctggatacacctt tggaaccagcagtgatgttgggagttataaccttcaccggctactatatgcactgggtgcgac gtctcctggtaccaacagcacccaggcaaagcaggcccctggacaagggcttgagtggatg ccccaaactcatgatttatgagggcagtaagcgggatggatcaaccctatcagtggtggcac gccctcaggggtttctaatcgcttctctggctccaaaactatgcacagaagtttcagggcagg agtctggcaacacggcctccctgacaatctctgggtcaccatgaccagggacacgtccatca gctccaggctgaggacgaggctgattattactggcacagcctacatggacctgagcaggct ctgctcatatgcaggtagtagcactttggtattcggagatctgacgacacggccgtgtattact gcggagggaccaagctgaccgtcctaggtgcgagaggaacgtattactatgatagt agtggttacatcccatttgactactggggccagggaaccctggtcaccgtctcctcag 183 caggttcagctggtgcagtctgggtctga 241tcctatgagctgactcagccactctcagtgtca 243 gttgaagaagcctggggcctcagtgaaggtggccctgggacagacggccagtattacctg gtttcctgcaaggcttctggatacaccttcatgggggaaacaacattggaagtaaaaatgtgc gtagctatgctatgacttgggtgcgacagactggtaccagcagaagccaggccaggcccct gcccctggacaagggcttgagtggatgggtgctggtcatctatagggatagcaaccggcc gatggatcaacaccaacactgggaacccctctgggatccctgagcgattctctggctccaa aacgtatgcccagggcttcacaggacggtctcggggaacacggccaccctgaccatcagc ttgtcttctccttggacacctctgtcagcacagagcccaagccggggatgaggctgactata ggcatatctgcagatcagcagcctaaaggactgtcaggtgtgggacagcagcgtggtattc ctgaggacactgccgtgtattactgtgcgaggcggagggaccaagctgaccgtcctag gagctctgggatattgtagtagtaccagctgctatcccgcttgggctgcttttgatatctg gggccaagggacaatggtcaccgtctctt cag 222gaggtgcagctggtggagtctggaggag 251 gatgttgtgatgactcagtctccaggcaccctg 253gcttgatccagccgggggggtccctgaga tctttgtctccaggggaaagagccaccctctccctctcctgtgcagcctctgggctcaccgtc tgcagggccagtcagagtgttcccagcagctaagtagcaactacatgagttgggtccgcca cttagcctggtaccagcagaaacctggccagggctccagggaaggggctggagtgggt gctcccaggctcctcatctatggtgcatccaccctcagttatttatagtggtggtagcacgttct agggccactggcatcccagacaggttcagtgacgcagactccgtgaagggccgattcac gcagtgggtctgggacagacttcactctcacccatctccagagacaattccaagaacacgct atcagcagactggagcctgaggattttgcagtgtatcttcaaatgaacagcctgggagccg gtattactgtcagcactatgatacctcaccccgtaggacacggccgtgtattactgtgcgaga ttcggcggagggaccaaagtggatatcaaacggagaaggtagtcctggaaactggttcga cccctggggccagggaaccctggtcacc gtctcctcag253 caggtccagctggtacagtctgggcctga 261 gacatccagatgacccagtctccaggcaccctg263 ggtgaagaagcctgggacctcagtgaag tctttgtctccaggggaaggagccaccctctcctgcgtctcctgcaaggcttctggattcaccttta agggccagtcagagtgttagcagcagctacttagctacctctgctgtgcagtgggtgcgacag cctggtaccagcagaaacctggccaggctcccagctcgtggacaacgccttgagtggatagg ggctcctcatctatggtgcatctagtggggccactatggatcgtcgttggcagtggtaacacaa ggcatcccagacagattcagtggcagtgggtctactacgcacagaagttccaggaaagagt gggacagacttcactctcaccatcagcagactgcaccattaccagggacatgtccacaacca gagcctgaagattttgcagtgtattactgtcagcacagcctacatggagctgagcagcctgag gtatggtagctcaccttacacttttggccaggggatccgaggacacggccgtgtatttctgtgc accaaggtggaaatcaaacggcgcctcattgtaatagtaccagctgcta tgacgcttttgatatctggggccaagggacaatggtcaccgtctcttcag 269 caggtgcagctggtggagtctggaggagg 271gccatccagttgacccagtctccttccttcctgtct 273cttgatccagcctggggggtccctgagactct gcatctataggagacagagtcaccatcacttgcccctgtgcagcctctgggctcaccgtcaatag gggccagtcagggcattagcagttatttagcctggaactacatgagctggatccgccaggctcc gtatcagcaaaaaccagggaaagcccctaagcagggaaggggctggagtgggtctcagttat tcctgatctatgctgcatccactttgcaaagtgggttatagcggtggtagtacattttacgcagact gtcccatcaaggttcagcggcagtggatctgggccgtgaagggccgattcaccatctccagag acagaattcactctcacaatcagcagcctgcagcacaattccaagaacacactgtctcttcaaat ctgaagattttgcatcttattactgtcaacagcttagaacagcctgagagccgaggacacggcc atagttaccccgctccggttttcggccctgggacatttattactgtgcgagagacttctacgagg caaagtggatatcaaacgttcttttgatatctggggccaagggacaatg gtcaccgtctcttcag 278caggtacagctggtgcagtctggggctga 281 gacatccagatgacccagtctccatcctccctg 283ggtgaagaagcctggggcctcagtgaag tctgcatctgtaggagacagactcaccatcactgtctcctgcaaggcttctggttacatctttat tgccgggcaagtcagagcattgccagctatttcagatatggtattagctgggtgcgacagg aaattggtatcagcagaaaccagggaaagcccccctggacaagggcttgagtggatggg cctaagctcctgatctatgctgcatccagtttgcatggatcagcgctaacaatggttacacaa aaagtggggtcccatcaaggttcagtggcagtactatgcacagaagctccagggcagagt ggatctgggacagatttcactctcaccatcagccaccatgaccacagacacatccacgagc agtctgcaacctgaagattttgcaacttaccactacagcctacatggagctgaggagcctga gtcaacagagttacagtaccctcggaatcacttgatctgacgacacggccgtgtattactgtgc tcggccctgggaccaaagtggatatcaaacgagagatgggggtattttgactggttatctc gactactttgaccactggggccagggaaccctggtcaccgtctcctcag 281 caggtgcagctggtggagtctgggggagg 291gatattgtgatgacccagactccactctcctcac 293 cttggtccagcctggggggtccctgagactctgtcacccttggacagccggcctccatctcctg ctcctgtgcagcctctggattcccctttagtacaggtctagtcaaagcctcgtacacagggatgg tctattggatgagctgggtccgccaggctcaaacacctacttgagctggcttcagcagaggcc cagggaaggggctggagtgggtggccaaaggccagcctccaagactcctaatttataagattt cataaagcaagatggaagtgagaaatactatctaaccggttctctggggtcccagacagattcag gtggactctgtgaagggccgattcaccatcttggcagtggggcagggacagatttcacactgaa ccagagacaacgccaagaactcactgtatcaatcagcagggtggaagctgaggatgtcgggg tgcacatgaacagcctgagaggcgaggactttattactgcatgcaagctacacaatttcctcatg acggctgtgtattactgtgcgagccgatattggtacacttttggccaggggaccaaggtggag acgattttcgaccggaggcttggtttgacta atcaaacctggggccagggaaccctggtcaccgtct cctcag 282 caggtgcagctgcaggagtctgggggag301 gaaattgtgttgacgcagtctccaggcaccct 303 gcttggtccagcctggggggtccctgagagtctttgtctccaggggaaaaagtcaccctctc ctctcctgttcagcctctggattcaccgtcactgcagggccagtcagagtgttagcagcacct gtagcaactacatgacctgggtccgccagacttagcctggtaccagcagaaacctggccag gctccagggaaggggctggagtgggtctgctcccaggctcctcatctatggtgcatccagc cagttatttatagcggtggtagcacattctaagggccactggcgtcccagacaggttccgtg cgcagactccgtgaagggcagattcaccgcagtgggtctgggacagacttcactctcacc atctccagagacaattccaagaacacgctgtatcagcagactggagcctgaagattttgcagt atcttcaaatgaacagcctgagagccgaggtattactgtcagcagtatggtagctcgctgtac gacaccgctgtgtattactgtgcgagagatacttttggccaggggaccaaagtggatatcaa ctggaagaggccgggggatttgactactg acgggccagggaaccctggtcaccgtctcct cag 285 cagctgcagctgcaggagtcgggcccag 311gacatccagatgacccagtctccatcctccctg 313 gactggtgaagccttcggagaccctgtcctctgcatctgtaggagacagagtcaccatcact ctcacctgcactgtctccggtgactccgtctgccgggcaagtcagagcattagcagctattt agtaattactactggagctggatccggcaaaattggtatcagcagaaaccagggaaagcc gcccgccgggaagggactggagtggattcctaagctcctgatctatgctgcatccagtttgc gggcgtatctataccagtgggagcaccaaaaagtggggtcccgtcaaggttcagtggcagt ctacaacccctccctcaagagtcgagtcacggatctgggacagatttcactctcaccatcaac catgtcagtagacacgtccaagaaccagttagtctgcaacctgaagattttgcaacttactact ctccctgaagctgagctctgtgaccgccggtcaacagagttacagtacccccgcgctcact cggacacggccgtgtattactgtgcgagagttcggcggagggaccaaagtggatatcaaac atcaccgggcttcccggtatagcagtggctggtacgaatggtggaactgcttcgaccc ctggggccagggaaccctggtcaccgtc tcctcag 316caggttcagctggtgcagtctggggctga 321 caggctgtgctgactcagcctccctccgcgtc 323ggtgaagaagcctggggcctcagtgaagg cgggtctcctggacagtcagtcaccatctcctgtctcctgcaaggcttctggatacaccttcac cactggaaccagcagtgacgttggtggttatacggctactatatgcactgggtgcgacagg actatgtctcctggtaccaacagcacccaggccccctggacaagggcttgagtggatggg aaagcccccaaactcatgatttatgaggtcagtatggatcaaccctaacagtggtggcacaa aagcggccctcaggggtccctgatcgcttctcactatacacagaagtttcagggcagggtc tggctccaagtctggcaacacggcctccctgaaccatgaccagggacacgtccatcagca ccgtctctgggctccaggctgaggatgaggctcagcctacatggagctgagcaggctgag gattattactgcagctcatatgcaggcagcaacatctgacgacacggccgtgtattcctgtgc cattgggtgttcggcggagggaccaagctgagagagatatggcgtttagtatggttcggggtt ccgtcctag cctttgactactggggccagggaaccctggtcaccgtctcctcag 318 caggtgcagctggtgcagtctgggcctga 331gccatccggatgacccagtctccaggcaccct 333 ggtgaagaagcctgggacctcagtgaaggtctttgtctccaggggaaagagccaccctctc gtctcctgcaaggcgtctggattcacccttctgcagggccagtcagagtgttagcagcagcta actagctctgctatgcagtgggtgcgacacttagcctggtaccagcagagacctggccag ggctcgtggacaacgccttgagtggataggctcccaggctcctcatctatggtacatccagc gatggatcgtcgttggcagtggcaacacaagggccactggcatcccagacaggttcagtg aactacgcacagaagttccaggaaagagtgcagtgggtctgggacagacttcactctcacc caccattaccagggacatgtccacaagcaatcagcagactggagcctgaagattttgcagt cagcctacatggagctgagcagcctgaggtattactgtcagcagtatggttactcagtgtac atccgaggacacggccgtgtattattgtgcacttttggccaggggaccaaagtggatatcaa ggccggccgtggctacaattcggactttg acactactggggccagggaaccctggtcac cgtctcctcag 334caggtgcagctggtggagtctgaggctga 341 gaaatagtgatgacgcagtctccagccaccct 343ggtgaagaagcctggggcctcagtgaag gtctttgtctccaggggaaagagccaccctctcgtttcctgcaaggcatctggatacaccttca ctgcagggccagtcagagtgttagtagctacttaccagctactatatgcactgggtgcgacag gcctggtaccaacagaaacctggccaggctcgcccctggacaagggcttcagtggatgg ccaggctcctcatctatgatgcatccaacagggaataatcaaccctagtgctggtagcaca gccactggcatcccagccaggttcagtggcaagctacgcacagaagttccagggcagag gtgggtctgggacagacttcactctcaccatcatcaccatgaccacggacacgtccacgacca gcagcctagagcctgaagattttgcagtttattacagtctacatggagctgagcagcctgaga ctgtcagcagcgtcgcaactggctattcactttctctgaggacacggccgtgtattactgtgcg ggccctgggaccaaagtggatatcaaacagagattctgtactagtaccagctgctaatg cttttgatatctggggccaagggacaatggtcaccgtctcttcag 361 caggtgcagctggtgcagtctggggctga 351gccatccggatgacccagtctccttccaccctg 353 ggtgaagaagcctggggcctcagtgaagtctgcatctgtaggagacagagtcaccatcact gtttcctgcaaggcttctggagacaccttctgccgggccagtcagagtattagtggctggtt actagctatactctgcattgggtgcgccagggcctggtatcagcagaaaccagagaaagcc gcccccggacaaaggcttgagtggatggcctaagctcctgatctatgatgcctccaatttgga gatggatcaacgctggcaatggttacacaaagtggggtcccatcaaggttcagcggcagt aaatattcacagaagttccagggcagagtcggatctgggacagaattcactctcaccatcaac accattaccagggacacatccgcgagcacagcctgcagcctgatgattttgcaacttattact agcctacatggagctgagcagcctgagatgccaacagtataatagttacccgtggacgttcg ctgaagacacggctgtgtattactgtgcgagccaagggaccaaagtggatatcaaac aatgtactatgatagtagactactttgactactggggccagggaaccctggtcaccgtctc ctcag 382 gaggtgcagctggtgcagtctggggctg 361cagcctgtgctgactcagccaccctcagtgtc 363 aggtgaagaagcctggggcctcagtgaaagtggccccaggaaagacggccaggattac ggtctcctgcaaggcttctgggtacaccttctgtgggggaagcaacattggaagtaaaagtg caccagttatgatatcaactgggtgcgacatgcactggtaccagcagaagccaggccaggcc ggccactggacaagggcttgagtggatgcctgtgctgatcatctattatgatagcgaccggc ggatggatgaaccctcacagtgataccaccctcagggatccctgagcgattctctggctcc aggctatgcacagaagttccagggcagaaactctgggaacacggccaccctgaccatca gtcaccatgaccaggaacacctccataacgcagggtcgaagccggggatgaggccgact cacagcctacatggagctgagcagcctgtttactgtcaggtgtgggatagtagtactgatca agatctgaggacacggccgtgtattactgttgtggtattcggcggggggaccaagctgacc gctcagggacccatagcagtgaactacat gtcctagggacgtctggggcaaagggaccacggtc accgtctcctca 384gaggtgcagctggtggagtctgggggag 371 gacatccagttgacccagtctccatcctccctg 373gcttggtcaagcctggagagtccctgaga tctgcatctgtaggagacagagtcaccatcactctctcctgtgcagcctctggattcaccttca tgccgggcgagtcagggcattagcaattatttagtgactactacatgacctggatccgccag gcctggtatcagcagaaaccagggaaagttccgctccagggaaggggctggagtgggttt taagctcctgatctatgctgcatccactttgcaatcatacattaggagtagtggtcatactatata caggggtcccatctcggttcagtggcagtggactacgcagactctgtgaagggccgattca tctgggacagatttcactctcaccatcagcagcccatctccagggacaacgccaagaactc ctgcagcctgaagatgttgcaacttattactgtcactgtatctacaaatgaacagcctgagagtc aaaagtataacaatgccctcgggacgttcggcgaggacacggccgtgtattactgtgcgag caagggaccaaggtggagatcaaacaggaggggttttacgatttttggagtggcc tctcaatgcttttgatatctggggccaagggacaatggtcaccgtctcttcag 394 gaggtgcagctggtgcagtctggggctg 381cagtctgtcgtgacgcagcctgcctccgtgtct 383 aggtgaagaagcctggggcctcagtgaagggtctcctggacagtcgatcaccatctcctgc ggtctcctgcaaggcttctggatacaccttactggaaccagcagtgacgttggtggttataa caccggctactatatgcactgggtgcgacctttgtctcctggtaccaacagcacccaggcaa aggcccctggacaagggcttgagtggatagcccccaaactcatgatttatgaggtcagtaa gggatggatcagccctaacagtggtggctcggccctcaggggtttctaatcgcttctctggc acaaactatgcacagaagtttcagggcagtccaagtctggcatcacggcctccctgaccatc ggtcaccatgaccagggacacgtccatcatctgggctccaggctgaggacgaggctgatta ccacagcctacatggacctgagcaggctttactgcaactcatatacaagcaacagtactcg gagatctgacgacacggccgtgtattactgtggtattcggcggagggaccaagctgaccgtc gcgagaggttattactatgaagccctcgatg ctagcttttgatatctggggccaagggacaatgg tcaccgtctcttcag 398caggtgcagctggtggagtctgggggag 391 cagactgtgctgactcagcctgcctccgtgtct 393gcttggtccagcctggggggtccctgaga gggtctcctggacagtcgatcaccatctcctgcctctcctgtgcagcctctggattcaccgtca actggaaccagcagtgacgttggtggttacaagtagcaactacatgacctgggtccgccagg ctatgtctcctggtaccaacagcacccaggcactccagggaaggggctggagtgggtctca aagcccccaaactcatgatttatgaggtcactagttatttatagcggtggtagcacatactacg agcggccctcaggggtccctgatcgcttctctcagactccgtgaagggcagattcaccatc ggctccaagtctggcaacacggcctccctgactccagagacaattccaagaacacgctatat cgtctctgggctccaggctgaggatgaggctgcttcaaatgaacagcctgagagccgacg attattactgcagctcatatgcaggcagcaacaacacggctgtatattactgtgcgagagact attgggtgttcggcggagggaccaagctgacctacagccgattacgatttttggagtggtta cgtcctag ttatgtaggtgcttttcatatctggggccaagggacaatggtcaccgtctcttcag

Amino Acid Sequences of CDRs

Heavy chain CDR SEQ SEQ SEQ Ab ID ID ID number CDR1-IMGT NO. CDR2-IMGTNO. CDR3-IMGT NO. 2 GGTFSNYA 5 IIPIFGTA 6 AGGGRYCSGGRC 7 HSAYSAY 22GFTFSNYA 15 ISSSGDIT 16 VKDVTRTYYVVF 17 DY 40 GFTVSRNY 25 IYSGGST 26ARDLFHRSGYHD 27 Y 44 GFTFSNYG 35 VWYDGSKK 36 ARDFAVGEEIADS 37 45GFTFSTYA 45 LSYDGSNK 46 AKGGSYAYYYY 47 MDV 54 GGSVSSGS 55 MYFSGST 56ARGDYDFWSGPP 57 YY GRVDV 55 GFTFTSSA 65 IVVGSGNT 66 AAPACGTSCSDAF 67 DI58 GFTFDDYA 75 VSWNSGTI 76 AREVGGTFGVLIS 77 REGGLDY 61 GGSVSSGN 85IYYTGSP 86 AREIYYYDRSGSY 87 FY NSDAFDI 75 GFTFNNYP 95 ISQDGGNK 96ARDVVVVVAAR 97 NHYYNGMDV 88 GGSISSGSY 105 IYNSGST 106 ARHCSGGTCYPK 107 NYYYGMDV 111 GGSISSNSY 115 IYYTGST 116 ARHVRAYDYDAP 117 F FDI 132GGSFSGYY 125 INHSGST 126 ARTDYYDSID 127 140 GFTFSTYD 135 IGTAGDT 136ARGSGTYFYYFD 137 Y 148 GGSISSSYY 145 VYYSGST 146 ARLMTTEDYYSG 147 MDV150 GVTVSSNY 155 IYSGGTT 156 ARDLMVYGIDV 157 158 GVTVSSNY 165 IYPGGST166 ARDLGSGDMDV 167 159 GFTFSSYG 175 ISYDGGNR 176 AKDRDDGWDWY 177 YFMDV165 GFTFTSSA 185 IVVGSGNT 186 AAPHCIGGSCHD 187 AFDI 170 GYSFTSYW 195IYPGDSDT 196 ARLGNWLVDY 197 175 GLTVSRNY 205 TYSGGST 206 ARDLRGEV 207177 GFTFSNYD 215 IGTAGDT 216 ARGQHTQIGHYY 217 YYYMDV 181 GFTVSSNY 225VYGGGTT 226 ATDNGYSYGFSF 227 DY 182 GYTFTGYY 235 INPISGGT 236ARGTYYYDSSGYI 237 PFDY 183 GYTFSSYA 245 INTNTGNP 246 ARALGYCSSTSCY 247PAWAAFDI 222 GLTVSSNY 255 IYSGGST 256 ARGEGSPGNWFD 257 P 253 GFTFTTSA265 IVVGSGNT 266 AAPHCNSTSCYD 267 AFDI 269 GLTVNRNY 275 IYSGGST 276ARDFYEGSFDI 277 278 GYIFIRYG 285 ISANNGYT 286 ARDGGILTGYLD 287 YFDH 281GFPFSIYW 295 IKQDGSEK 296 ASRYYDFRPEAW 297 FDY 282 GFTVSSNY 305 IYSGGST306 ARDLEEAGGFDY 307 285 GDSVSNYY 315 IYTSGST 316 ARDHRASRYSSG 317WYEWWNCFDP 316 GYTFTGYY 325 INPNSGGT 326 ARDMAFSMVRGS 327 FDY 318GFTLTSSA 335 IVVGSGNT 336 AAGRGYNSDFDY 337 334 GYTFTSYY 345 INPSAGST 346ARDSVLVPAANA 347 FDI 361 GDTFTSYT 355 INAGNGYT 356 AKCTMIVDYFDY 357 382GYTFTSYD 365 MNPHSDTT 366 AQGPIAVNYMDV 367 384 GFTFSDYY 375 IRSSGHTI 376ARGGVLRFLEWP 377 LNAFDI 394 GYTFTGYY 385 ISPNSGGT 386 ARGYYYEALDAF 387DI 398 GFTVSSNY 395 IYSGGST 396 ARDSTADYDFWS 397 GYYVGAFHI

Light Chain CDR SEQ SEQ SEQ Ab ID ID ID number CDR1-IMGT NO. CDR2-IMGTNO. CDR3-IMGT NO.   2 QSVSSSY   8 GAS   9 QQYGSSLT  10  22 QSISSY  18AAS  19 QQSYTTPYT  20  40 QDINNY  28 DAS  29 QQYDNLPA  30  44 ALPKKY  38EDS  39 YSRDSSGDHWV  40  45 QDISNY  48 DAS  49 QQYDNLPLT  50  54 QSVSSSY 58 GAS  59 QHYGSSPVT  60  55 QSVSSSY  68 GAS  69 QQYGSSPWT  70  58TIGSKS  78 DDS  79 QVWDSSSDRVV  80  61 QSVSSN  88 GAS  89 QQYNNWPPLT  90 75 QGISSW  98 AVS  99 QQAKSFPFT 100  88 SSNIGNNA 108 YDD 109AAWDDSLNVVV 110 111 QGIRND 118 AAS 119 LQINSYPLT 120 132 TGAVTSGHY 128DTR 129 LLSSSGARV 130 140 QSINNY 138 AAS 139 QQSYSAPPWT 140 148 QGISDY148 AAS 149 QQYHSYPIT 150 150 QGISSY 158 AAS 159 QQLDSYPPGYT 160 158QGISSY 168 AAS 169 QQLNSYRYT 170 159 QSISGNY 178 GAS 179 QQYGSSYT 180165 QSVRSSY 188 GAS 189 QQYGSSPWT 190 170 QSLLHSDGKTY 198 EVS 199MQSIQLPRGIT 200 175 QDISNF 208 DAS 209 HQYDNLPRT 210 177 QSISSY 218 AAS219 QQSYSNPPEGS 220 181 SSDVGGYNL 228 EGS 229 CSYAGSSNWV 230 182SSDVGSYNL 238 EGS 239 CSYAGSSTLV 240 183 NIGSKN 248 RDS 249 QVWDSSVV 250222 QSVPSSY 258 GAS 259 QHYDTSPR 260 253 QSVSSSY 268 GAS 269 QQYGSSPYT270 269 QGISSY 278 AAS 279 QQLNSYPAPV 280 278 QSIASY 288 AAS 289QQSYSTLGIT 290 281 QSLVHRDGNTY 298 KIS 299 MQATQFPHGYT 300 282 QSVSSTY308 GAS 309 QQYGSSLYT 310 285 QSISSY 318 AAS 319 QQSYSTPALT 320 316SSDVGGYNY 328 EVS 329 SSYAGSNHWV 330 318 QSVSSSY 338 GTS 339 QQYGYSVYT340 334 QSVSSY 348 DAS 349 QQRRNWLFT 350 361 QSISGW 358 DAS 359QQYNSYPWT 360 382 NIGSKS 368 YDS 369 QVWDSSTDHVV 370 384 QGISNY 378 AAS379 QKYNNALGT 380 394 SSDVGGYNF 388 EVS 389 NSYTSNSTRV 390 398 SSDVGGYNY398 EVT 399 SSYAGSNNWV 400

Amino Acid Sequence of Heavy Chain and Light Chain Variable Regions ofSelected Antibodies

SEQ SEQ Antibody Heavy chain ID Light chain ID number:Amino Acid Sequence NO: Amino Acid sequence NO: Beta 6 EVQLVESGPGLVKPSET402 EIVMTQSPATLSLSPGERAT 404 LSLTCTVSGGSISSSSHY LSCRTSQSVTSYLAWYQQRWGWIRQPPGKGLEWIGS PGQAPRLLIYDASDRATGIP IYYSESAYYNPSLKSRVTARFSGSGSGTDFTLTISNLE MSIDTSKNQFSLKLNSVT PEDFAVYYCQLRSNWPPITAADTAVYYCARVTEPR FGQGTRLETK WTSCYFDYWGQGTLVT VSS Beta 10EVQLVESGPGLVKPSET 412 DIQMTQSPSFLSASVGDRV 414 LSLTCTVSGGSISSSSYYTITCRASQGISSYLAWYQQ WGWIRQPPGKGLEWIGS KPGKAPKLLIYAASTLQSGIYYSGSTYYNPSLKSRVT VPSRFSGSGSGTEFTLTISSL ISVDTSKNQFSLKLSSVTQPEDFATYYCQQLNTYPSI AADTAVFFCARERSAPL TFGQGTRLEIK AGNWFDPWGQGTLVTV SSBeta 20 EVQLVESGGGVVQPGRPLRL 422 AIQLTQSPGTLSLSPGERATLS 424SCAASGFPFSNYGMHWVR CRASQSVSSSYLAWYQQKPG QAPGKGLEWVAVIWYDGSQAPRLLIYGASSRATGIPGRFS NKYYADSVKGRFTISRDNS GSGSGTDFTLTISRLEPEDFAVKNTLYLQMNNLRAEDTAIY YYCQQYGSSPGITFGGGTKV YCAKDGYTAHYYYYYMDV DIKWGKGTTVTVSS Beta 22 EVQLVESGGGVVQPGRSL 432 AIQMTQSPDSLAVSLGERATI 434RLSCAASGFTFSNYGIHWV NCKSSQSILYNSNNKTYLAW RQAPGKGLEWVAVISYDGYQQKPGQPPKLLIFWASTRES SHKYYADSVKGRFTISRDN GVPDRFSGSGSGTDFTLTISSLSKNTLYLQMNSLKTEDTA QAEDVAVYYCQQYYSIPLIFG VYYCAKDSSAAIPYYYYG PGTKVDIKMDVWGQGTTVTVSS Beta 23 QLQLQESGPGLVKPSETLSL 442 SYELTQPPSVSVSPGQTASITCS444 TCTVSGGSISSSSYYWGWIR GHKLGDKNACWYQQKPGQSP QPPGKGLEWIGNVYYSGGTVLVIYEYNKRPSGIPERFSGSNS YCNPSLKSRVTISVDTSKNQ GNTATLTISGTQAMDEADYYCFSLNLSSVTAADTAVYYCA QAWDTGTHVFGTGTKVTVL RIWFGEPAGGYFDYWGQG TLVTVSSBeta 24 QVQLVQSGPGLVKPSQTLS 452 SYELTQPASVSGSPGQSITISCT 454LTCSVSDGSISSSDYYWSW GTSIDVGNYNLASWYQQHPGK IRQPPGKGLEWIGYIYYTGAPKLIIYEGSRRPSGVSNRFSGA STYYNPSLKSRVSISVDRS KSGNTASLTISGLQAEDEADYYKNQFSLKLSSVTAADTAVY CCSYVGSSTYVFGSGTKVTVL YCARLVVPSPKGSWFDPW GQGTLVTVSSBeta 25 QVQLVQSGPEVKKPGTSVK 462 EIVMTQSPGTLSLSPGERATLS 464VSCKASGFTFTSSAMQWVR CRASQSVSSSYLAWYQQKPG QARGQRLEWIGWIVVGSGNQAPRLLIYGASSRATGIPDRES TNYAQKFQERVTITRDMST GSGSGTDFTLTISRLEPEDFAVSTAYMELSSLRSEDTAVYY YYCQQYGSSPFTFGGGTKVEI CAAVYCSGGSCNDAFDIWG KQGTMVTVSS Beta 26 QVQLQQSGPGLVKPSETLSL 472 SYELTQPPSVSVAPGQTARIT 474TCTVSGASISNYYWSWIRQP CGGNNIGSKSVHWFQQKPGQ PGKGLEWVGYIYYTGSTNHAPVLVVYDDSDRPSGIPERFS NPSLKSRVTISLDTSKNQFS GSNSGNTASLTISRVEAGDEALRLSSVTAADTAVYYCARA DYYCQVWDSASDSGVFGTGT YCSGGSCFDTFDIWGQGTM KLTVP VTVSSBeta 27 EVQLLESGGGLVQPGGSLR 482 DIQMTQSPGTLSLSPGERATLS 484LSCAASGLTVRSNYMNWV CRASQSVSSSSLAWYQQKHGQ RQAPGKGLEWVSLIYSGGSAPRLLIYGTSSRATGIPDRFSGS TFYADSVKGRFTISRHDSKN GSGTDFTLTISGLEPEDFA VYYTLYLQMNSLRAEDTAVYYC CQQYGSSPLFGGGTKVEIK ARDLVVYGMDVWGQGTT VTVSS Beta 29EVQLVESGGGVVQPGRSL 492 DIQLTQSPDSLAVSLGERATIN 494 RLSCAASGFTFSNYGMHRVCKSSQSVLYSSNNKNYLAWY RQAPGKGLEWVALISYEES QQKPGQPPKLLIYWASTRESGNRYYGDSVRGRFTISRDNS VPDRFSGSGSGTDFTLTISSLQ KNTLYLQMNSLRPEDTAVAEDVAVYYCQQYFGSPSITFG YYCAKDQGPATVMVTAIR QGTRLEIK GAMDVWGQGTTVTVSSBeta 30 QVQLVQSGAEVKKPGASV 502 DVVMTQSPSSLSASVGDRVT 504KVSCKASGYTFTDYYMH VTCRASQGIRNDLGWYQQKP WVRQAPGQGLEWMGWINGKAPKRLIYAASSLQSGVPSR SKDGGANYAQKFQGRVTL FSGSGSGTDFTLTISSLQPEDFTRDTSIDTAYIELSRLRSDD ATYYCLQHNSYLRFTFGPGTK TAVYYCARSASTVTEPPTN VDIKWFDPWGQGTLVTVSS Beta 32 EVQLVQSGAEVKKPGASVK 512 DIQMTQSPSSVSASVGDRLTIT514 VSCKASGYTFTGYYMHWV CRASQGISSWLAWYQQKPGK RQAPGQGLEWMGWINPNSAPKLLIYAASSLQSGVPSRFSG GGTNYAQKFQGRVTMTRD SGSGTDFTLTISSLQPEDFATYYTSITTGYMELSSLRSDDTAL CQQANSFPWTFGQGTKVEIK YYCARVGAHDYYDSSDNWFDPWGQGTLVTVFS Beta 33 QVQLVQSGAEVKKPGASV 522 QSALTQPPSVSVSPGQTARIT 524KVSCKASGYPLTGYYIHW CSGDALSKQHAYWYQQKPG VRQAPGQGLEWMGWLNPQAPVLVIYKDSERPSGIPERFS NSGGTKYAQKFQGRVTMT GSSSGTIVTLTISGVQAEDEARDTSISTGYMELSRLRSDD DYYCQSADNSGSRYVFGTGT TAVYYCARDGGGIDDYVQ KVTVLEDGMDVWGQGPMVTVSS Beta 34 EVQLVESGGGLVQPGGSL 532 DIQMTQSPATLSLSPGERATLS534 RLSCAASGFTFSSYSMNWV CRASQSVSTYLAWYQQKPGQ RQAPGKGLEWVSYISGINSAAPRLVIYDASNRATGIPARFSG IYYADSVKGRFTISRDNAK GGSGTDFTLTISSLEPEDFAVYYNSLYLQMNSLRVEDTAVY CQQRLNWPLTFGGGTKVDIK YCARDKYLGIKDMWGQG TMVTVSSBeta 38 EVQLVQSGAEVKKPGESL 542 QSVLTQPPSASGTPGQRVTIS 544KISCKGSGYSFTNYWIGWV CSGSSSNLGGNTVNWYQQLP RQMPGKGLEWMGIIYPGDGTAPKLLIYSNNQRPSGVPDR SGTRYSPSFQGQVTISADK FSGSKSGTSASLAISGLQSEDESIRTAYLQWSSLKASDSAM ADYYCAAWDDSLNGPVFGT YYCARSRVGATGGYYDYY GTKVTVLMDVWGQGTTVTVSS Beta 40 QVQLVESGPGQVKPSETLS 552 QSVLTQPPSVSVSPGQTARIT 554LTCTVSGGSISSSSYYWGW CSGDALSTQNGNWYQQKPG IRQPPGKGLEWIGSIYYSGSQAPVMVICKDSERPSGIPERFS AYYNPSLKSRVTISVDTSK GSRSGTTVTLTISGVQAEDEANQFSLKLNSVTAADTAVF DYHCQSADNRAHVVFGGGT YCARHAAPSPGDNWFDPW KLTVLGQGTLVTVSS Beta 43 EVQLVESGGGVVQPGRSLR 562 SYELTQPPSVSVAPGKTATIT 564LSCAASGFTFSSYGMHWVR CGGNNIGTKSVHWYQQKPG QAPGKGLEWVAVIWYDGSQAPVLVIYYNSDRPSGIPERFS NNFYADSVKGRFTISRDNF GSNSGNTVTLTISRVEAGDEAKNTLYLQMNSLRAEDTAV DYYCQVWDSGSDHYVFGTG YYCARSYCSGGFCFGYYYG TKVTVVLDVWGQGTTVTVSS Beta 44 QVQLVQSGAEVKKPGASV 572 QSVVTQPASVSGSPGQSITISCT574 KVSCKASGYTFTSYGISWV GTSSDVGSYNLVSWYQQHPGK RQAPGQGLEWMGWISPYNAPKLMIYAGSKRPSGVSNRFSG GNTHYAQKLQGRVTMTTD SKSGNTASLTISGLQAEDEADYTSTSTAYMELRSLRSDDTA YCCSYAGSSTWVFGGGTKLTV VYYCARDGELLGWFDPW L GQGTLVTVSSBeta 45 PGQLVESGGSLVQPGGALR 582 AIQLTQSPSSLSASVGDRVTIT 584LSCEASGFTFSDYAMSWV CQASQDIRNYLNWYQQKPGK RQAPGKGLEWVSVINSSGGAPKLLIYDASNLETGVPSRFS ITNYADSVKGRFTISRNNS GSGSGTDFTFTIGSLQPEDIATKNTLYLQMNSLRGDDTAI YYCQQYDNLRATFGGGTKVE YYCAKGPPRINTFYRHYYG IKMDVWGQGITVTVSS Beta 47 QVQLVESGPEMKKPGTSV 592 EIVLTQSPGTLSLSPGERATLS 594KVSCKASGFTFITSAVQWV CRASQSVSRNYLAWYQQKP RQARGQRLEWMGWIAVGGQVPRLLIYGASSRATGIPDR SQNTNYAQKFQDRVTINR FRGSGSGTDFTLTINRLESEDFDMSTSTAYMELSSLRSEDT AVYYCQQYGSSLFTFGPGTK AVYYCAAPHCNRTSCHDG VDIKFDIWGQGTMVTVSS Beta 48 EVQLVESGGGLVKPGESL 602 AIQMTQSLPPATLAPGERATL 604RLSCAASGFTFSSYAMNW SCRASQSVSNNLAWYQQKP VRQAPGKGLEWVSSISTGSGQAPRLLIYGASTRATGIPAR YFIYYSDSVKGRFTISRDN FSGSGSGTEFTLTISSLQSEDFAKNSLYLQMNSLRAADTA AVYYCQQYNNWPPWTFGQG IYYCARGKEDTSAAFDIW TKVDIKGQGTMVTVSS Beta 49 EVQLVQSGAEVKKPGSSV 612 AIRMTQSPGTLSLSPGERATLS 614KVSCKASGGTFSSSVISWV CRASQSVSSSYLAWYQQKPG RQAPGQGLEWMGGIIPLFGQAPRLLIYGASSRATGIPDRFS SANYAQKFQGRVTITADES GSGSGTDFTLTISRLEPEDFAVTSTAYMEMTSLRSEDTAV YYCQQYGTSPSWTFGQGTKV YYCAKVSQWALILFWGQG EIK TLVTVSSBeta 50 EVQLVQSGAEVKKPGSSV 622 DIVMTQSPGTLSLSPGERATL 624KVSCKASRGTFNTYVFTW SCRASQSFTSSYLAWYQQKP VRQAPGQGLEWMGGIIPFFGQAPRLLIYGASSRATGIPDRF GTADYAQKFQGRVTITAD SGTGSGTDFTLTISRLEPEDFADSTSTAYMELSSLRSEDTA VYYCQQYGTSPRMYTFGQGT VYYCSRLSQWDLLPMWG KVDIKQGTLVTVSS Beta 51 QLQLVESGAEVKKPGASVK 632 AIRMTQSPSSLSASVGDRVTI 634VSCKVSGYTLTELSMHWVR TCRASQGIRNYLAWFQQKPG QAPGKGLEWMGGFDPEDGKAPKSLIYAASSLQSGVPSKF ETIYAQKFQGRVTMTEDTSI SGSGSGTDFTLTISSLQPEDFADTVYMELSSLRSEDTAVYY TYYCQQYNSYPLTFGQGTRL CAIDRKHWLVGLDYWGQG EIK TLVTVSSBeta 53 QVQLVQSGAEVKKPGESL 642 DIQMTQSPATLSVSPGERATL 644RISCKGSGHNSPSYWISWV SCRASQSVSSTLAWYQQKPG RQMPGKGLEWMGRIDPSDQAPRLLIYGASTRATGIPARFS SYTNYSPSFQGHVTISADK GSGSGTEFTLTISSLQSEDFAVSISTAYLQWSSLQASDTAI YYCQQYNNWSTWTFGQGTK YYCARHVVALTHLYPDY VDIKWGQGTLVTVSS Beta 54 QVQLQESGPGLVKPSETLS 652 DIQLTQSPSFLSASVGDRVTIT 654LTCTVFGGSITSSNHYWV CRASQGISSYLAWYQQKPGK WIRQPPGKGLEWIGSMYYSAPKLLIYAASTLQSGVPSRFS GSTAYNPSLTNRVTISVDT GSGSGTEFTLTISSLQPEDFATSKNQFSLKLSSVTAADTAV YYCQQLNSYPLTFGGGTKVEI YYCARQIGPKRPSQVADW KFDPWGQGTLVTVSS Beta 55 QVQLQESGPGLVKPSETLS 662 AIRMTQSPSTLSASVGDRVTIA664 LTCTVSGDSISSSRYYWGW CRASQSISAWLAWYQQKPGKA IRQPPGKGLEWIGTFYYSGIPKLLIYKASSLESGVPSRFSGSG TYYNPSLKSRVTIFVDTSK SGTEFTLTINSLQPDDFATYYCNQFSLKLSSVTAADTAVYY QQYISSSPWTFGQGTKVEIK CARPRPPDYYDNSGALLFDIWGQGTMVTVSS Beta 56 QLQLQESGPGLVRPSQTLSL 672 QSALTQPASVSGSPGQSITISCT674 SCTVSGGSISSATHYWSWIR GTSSDVSGYNYVSWYQQHPD QHPGRGLEWIGYIYYTGGTKAPKLLIYDVTNRPTGVSNRFS FYNPSLKSRLTISVDTSKNQ ASKSGNTASLTISGLQAEDEADFSLKLSAVTAADTAVYYCA YYCSSDTNSIPRYVVFGGGTKL RVIAARPGSTYFDFWGRGTL TVLVTVSS

Nucleotide Sequence of Heavy Chain and Light Chain Variable Regions ofSelected Antibodies

SEQ SEQ Antibody Heavy chain NO: Light chain ID number:Nucleotide Sequence ID Nucleotide sequence NO: Beta 6gaggtgcagctggtggagtcgggcccag 401 gaaatagtgatgacgcagtctccagccaccct 403gactggtgaagccttcggagaccctgtccc gtctttgtctccaggggaaagagccaccctctcctcacctgcactgtctctggtgggtccatcag tgcaggaccagtcagagtgttaccagctacttacagtagtagtcactactggggctggatccg gcctggtaccaacagagacctggccaggctcccagcccccagggaaggggctggagtgg ccaggctcctcatctatgatgcatccgacagggattgggagtatttattatagtgagagtgcctact ccactggcatcccagccaggttcagtggcagtgacaacccgtccctcaagagtcgagtcacca ggtctgggacagacttcactctcaccatcagcatgtcaatagacacgtccaagaaccagttctc acctagagcctgaagattttgcagtttattactgtccctgaagctgaactctgtgaccgccgcgga agctgcgtagcaactggcctccgatcaccttccacggccgtgtattactgtgcgagagtcact ggccaagggacacgactggagactaaacgagcctcggtggacttcttgttactttgactac tggggccagggaaccctggtcaccgtctc ctcagBeta10 gaagtgcagctggtggagtcgggcccag 411gacatccagatgacccagtctccatccttcctg 413 gactggtgaagccttcggagaccctgtccctctgcatctgtaggagacagagtcaccatcact tcacctgcactgtctctgggggctccatcagtgccgggccagtcagggcattagcagttattta cagtagtagttactactggggctggatccggcctggtatcagcaaaaaccagggaaagccc ccagcccccagggaaggggctggagtggctaagctcctgatctatgctgcatccactttgca attgggagtatctattatagtgggagcacctaagtggggtcccatcaaggttcagcggcagtg actacaacccgtccctcaagagtcgagtcagatctgggacagaattcactctcacaatcagca ccatatcagtagacacgtccaagaaccagtgcctgcagcctgaagattttgcaacttattactg tctccctgaagctgagctctgtgaccgccgtcaacagcttaatacttacccttcgatcaccttc cggacacggccgtgtttttctgtgcgagagggccaagggacacgactggagattaaac agaggagcgctcctctcgcgggcaactggttcgacccctggggccagggaaccctggt caccgtctcttcag Beta20gaagtgcagctggtggagtctgggggagg 421 gccatccagttgacccagtctccaggcaccctg 423cgtggtccagcctgggaggcccctgagac tctttgtctccaggggaaagagccaccctctccttctcctgtgcagcctctggattccccttcagt gcagggccagtcagagtgttagcagcagctacttaactatggcatgcactgggtccgccaggct agcctggtaccagcagaaacctggccaggctccccaggcaaggggctggaatgggtggcag caggctcctaatctatggtgcatccagcagggccttatatggtatgatggaagtaataaatactat actggcatcccaggcaggttcagtggcagtgggcagactccgtgaagggccgattcaccatc gtctgggacagacttcactctcaccatcagcagtccagagacaattccaagaacacgctgtat actggagcctgaagattttgcagtgtattactgtcctgcaaatgaacaacctgagagctgagga agcagtatggtagctcacctgggatcactttcggcacggctatatattactgtgcgaaagatggg cggagggaccaaagtggatatcaaactacacggcccactactactactactacatgg acgtctggggcaaagggaccacggtcacc gtctcctcaBeta22 gaagtgcagctggtggagtctgggggag 431 gccatccagatgacccagtctccagactccct433 gcgtggtccagcctgggaggtccctgag ggctgtgtctctgggcgagagggccaccatcactctcctgtgcagcctctggattcaccttc aactgcaagtccagccagagtattttatacaacagtaactatggcatacactgggtccgcca tccaacaataagacctacttagcttggtaccagggctccaggcaaggggctggagtgggt cagaaaccaggacagcctcctaagctgctcatggcagttatttcatatgatggaagtcataaa tttctgggcatctacccgggaatccggggtcctattatgcagactctgtgaagggccgattc ctgaccgattcagtggcagcgggtctgggacaccatctccagagacaattccaagaacac agatttcactctcaccatcagcagcctgcaggctgctatatctgcaaatgaacagcctgaaaa gaagatgtggcagtttattactgtcagcaatattactgaggacacggctgtgtattactgtgcga tagtattccccttattttcggccctgggaccaaaaagatagttcagctgctattccctactacta gtggatatcaaacctacggtatggacgtctggggccaaggg accacggtcaccgtctcttca Beta23cagctgcagctgcaggagtcgggccca 441 tcctatgagctgactcagccaccctcagtgtcc 443ggactggtgaagccttcggagaccctgtc gtgtccccaggacagacagccagcatcacctcctcacctgcactgtctctggtggctccat gctctggacataagttgggggataaaaatgcttgcagcagtagtagttactactggggctgga ctggtatcagcagaagccaggccagtcccctgtccgccagcccccagggaaggggctgg tgctggtcatctatgaatataacaagcggccctcagtggattgggaatgtctactatagtgggg agggatccctgagcgattctctggctccaactcgcacctactgcaacccgtccctcaagagt tgggaacacagccactctgaccatcagcgggcgagtcaccatatcagtagacacgtccaa acccaggctatggatgaggctgactattactgtgaatcagttctccctgaacctgagctccgt caggcgtgggacaccggcactcatgtcttcgggaccgccgcggacacggccgtgtattact aactgggaccaaggtcaccgtcctaggtgcgagaatatggttcggggagcctgc gggtgggtactttgactactggggccagggaaccctggtcaccgtctcctcag Beta24 caggtccagctggtacagtcgggcccag 451tcctatgagctgactcagcctgcctccgtgtct 453 gactggtgaagccttcacagaccctgtccgggtctcctggacagtcgatcaccatctcctgc ctcacctgctctgtctctgatggctccatcaactgggaccagcattgatgttgggaattataac gcagtagtgattactactggagctggatcccttgcctcctggtaccaacagcacccaggcaa gccagccccccgggaagggcctggagtgagcccccaaactcatcatttatgagggcagtag gattgggtacatctattacactgggagcacgcggccctcaggggtttctaatcgcttctctgg ctactacaacccgtccctcaagagtcgagcgccaagtctggcaacacggcctccctgaca tttccatatcagtagacaggtccaagaaccaatctctgggctccaggctgaggacgaggctga attctccctgaagctgagttctgtgactgccttattactgctgctcatatgtaggtagtagcactt gcagacacggccgtttactattgtgccagatgtcttcggatctgggaccaaggtcaccgtcct actcgtagtaccatctccgaagggctcctg aggttcgacccctggggccagggaaccctgg tcaccgtctcctcaa Beta25caggtccagctggtacagtctgggcctga 461 gaaatagtgatgacgcagtctccaggcaccct 463ggtgaagaagcctgggacctcagtgaag gtctttgtctccaggggaaagagccaccctctcgtctcctgcaaggcttctggattcaccttta ctgcagggccagtcagagtgttagcagcagctactagctctgctatgcagtgggtgcgacag cttagcctggtaccagcagaaacctggccagggctcgtggacaacgccttgagtggatagg ctcccaggctcctcatctatggtgcatccagcagatggatcgtcgttggcagtggtaacacaa ggccactggcatcccagacaggttcagtggcactacgcacagaagttccaggaaagagt agtgggtctgggacagacttcactctcaccatccaccattaccagggacatgtccacaagca agcagactggagcctgaagattttgcagtgtatcagcctacatggagctgagcagcctgag tactgtcagcagtatggtagctcacccttcacttatccgaggacacggccgtgtattactgtg tcggcggagggaccaaggtggaaatcaaaccggcagtttattgtagtggtggtagctgta atgatgcttttgatatctggggccaagggacaatggtcaccgtctcttcag Beta26 caggtacagctgcagcagtcgggcccag 471tcctatgagctgacacagccaccctcggtgtca 473 gactggtgaagccttcggagaccctgtccgtggccccaggacagacggccagaattacctgt ctcacctgcactgtctctggtgcctccattagggggaaacaacattggaagtaaaagtgtgc gtaattattactggagttggatccggcagcactggttccagcagaagccaggccaggcccc ccccagggaagggactggagtgggttggtgtgctggtcgtctatgatgatagcgaccggcc atatatctattacactgggagcaccaaccactcagggatccctgagcgattctctggctccaa caacccctccctcaagagtcgagtcaccactctgggaacacggcctccctgaccatcagcag tatcactagacacgtccaagaatcagttctggtcgaagccggggatgaggccgactattact ccctgaggctgagctctgtgaccgctgcggtcaggtgtgggatagtgctagtgattcaggtg gacacggccgtctattactgtgcgcgagctcttcggaactgggaccaagctcaccgtccca ctattgtagtggtggtagctgcttcgatactt gttgatatctggggccaagggacaatggtc accgtctcttcag Beta27gaagtgcagctgttggagtctggaggag 481 gacatccagatgacccagtctccaggcaccct 483gcttggtccagcctggggggtccctgaga gtctttgtctccaggggaaagagccaccctctcctctcctgtgcagcctctgggttaaccgtc ctgcagggccagtcagagtgttagcagcagctcagaagcaactacatgaactgggtccgcca cttagcctggtaccagcagaaacatggccaggggctccagggaaggggctggagtgggtc ctcccaggctcctcatctatggtacatccagcagtcacttatttatagcggtggtagtacattcta ggccactggcatcccagacaggttcagtggccgcagactccgtgaagggccgattcacc agtgggtctgggacagacttcactctcaccatcatctccagacacgattccaagaacacact agtggactggagcctgaagattttgcagtgtatgtatcttcaaatgaacagcctgagagctga tactgtcagcagtatggtagctcaccccttttcgggacacggccgtgtattactgtgcgcgag gcggggggaccaaggtggaaatcaaacatttggtagtctacggaatggacgtctggg gccaagggaccacggtcaccgtctcctca Beta29gaggtgcagctggtggagtctggggga 491 gacatccagttgacccagtctccagattccctg 493ggcgtggtccagcctgggaggtccctga gctgtgtctctgggcgagagggccaccatcagactctcctgtgcagcctctggattcacctt actgcaagtccagccagagtgttttatacagctcagtaattatggcatgcaccgggtccgc ccaacaataagaactacttagcttggtaccagcaggctccaggcaaggggctggagtgg cagaaaccaggccagcctcctaaactcctcatgtggcacttatttcatatgaagaaagtaata ttactgggcgtctacccgggaatccggggtccgatattatggagactccgtgaggggccg ctgaccgattcagtggcagcgggtctgggacaattcaccatctccagagacaattccaaga gatttcactctcaccatcagcagcctgcaggctacactctgtatctgcaaatgaacagcctga gaagatgtggcagtatattactgtcagcaatattgacctgaggacacggctgtgtattactgt ttggttctccttcgatcaccttcggccaagggagcgaaagatcaaggcccggctactgtgat cacgactggagattaaacggtgactgctattcggggcgctatggac gtctggggccaagggaccacggtcacc gtctcctcagBeta30 caggtgcagctggtgcagtctggggctga 501gatgttgtgatgactcagtctccatcctccctgt 503 ggtgaagaagcctggggcctcagtgaagctgcatctgtaggcgacagagtcaccgtcacttg gtctcctgcaaggcttctggatacaccttcaccgggcaagtcagggcattagaaatgatttag ccgactactatatgcactgggtgcgacaggctggtatcagcagaaaccagggaaagctcc gcccctggacaagggcttgagtggatggtaagcgcctgatctatgctgcatccagtttgcaa gatggatcaactctaaagatggtggcgcgagtggtgtcccatcaaggttcagcggcagtgg aactatgcacagaagtttcagggcagggtatctgggacagacttcactctcacaatcagcag caccctgaccagggacacgtcaatcgaccctgcagcctgaagattttgcaacttattactgt acagcctacatagaactgagcaggctcagactacagcataatagttacctccgtttcactttcgg tctgacgacacggccgtgtattactgtgcgccctgggaccaaagtggatatcaaac agatccgcctctacagtaaccgaaccaccgacaaactggttcgacccctggggccag ggaaccctggtcaccgtctcctcag Beta32gaagtgcagctggtgcagtctggggctga 511 gacatccagatgacccagtctccatcttccgtg 513ggtgaagaagcctggggcctcagtgaag tctgcatctgtaggagacagactcaccatcactgtctcctgcaaggcttctggatacaccttca tgtcgggcgagtcagggtattagcagctggttccggctactatatgcactgggtgcgacag agcctggtatcagcagaaaccagggaaagccgcccctggacaagggcttgagtggatgg cctaagctcctgatctatgctgcatccagtttgcgatggatcaaccctaacagtggtggcaca aaagtggggtcccatcaaggttcagcggcagtaactatgcacagaagtttcagggcagggt ggatctgggacagatttcactctcaccatcagccaccatgaccagggacacgtccatcacc agcctgcagcctgaagattttgcaacttactattacaggctacatggagctgagcagcctga gtcaacaggctaacagtttcccgtggacgttcggatctgacgacacggccctgtattactgtg gccaagggaccaaggtggagatcaaaccgagagttggggctcacgattactatgata gtagtgacaactggttcgacccctggggccagggaaccctggtcaccgtcttctcag Beta33 caggtgcagctggtgcagtctggggctga 521caatctgccctgactcagccaccctcggtgtc 523 ggtgaagaagcctggggcctcagtgaagagtgtccccaggacagacggccaggatcacc gtctcctgcaaggcttctggataccccctctgctctggagatgcattgtcaaagcaacatgct accggctactatatacactgggtgcgacatattggtaccagcagaagccaggccaggccc ggcccctggacaaggacttgagtggatggctgtattggtgatatataaagacagtgagaggc gatggctcaaccctaacagtggtggcacacctcagggatccctgagcgattctctggctcca aagtatgcacagaagtttcagggcagggtgctcagggacaatagtcacgttgaccatcagtg caccatgaccagggacacgtccatcagcgagtccaggcagaagacgaggctgactattac acaggctacatggagctgagcaggctgagtgtcaatcagcagacaacagtggtagtagatat atctgacgacacggccgtgtactactgtgcgtcttcggaactgggaccaaggtcaccgtcct gagagatggggggggaatagatgattac aggttcaggaggacggtatggacgtctgggg ccaagggcccatggtcaccgtctcttca Beta34gaagtgcagctggtggagtctgggggag 531 gacatccagatgacccagtctccagccaccct 533gcttggtacagcctggggggtccctgag gtctttgtctccaggggaaagagccaccctctcactctcctgtgcagcctctggattcaccttc ctgcagggccagtcagagtgttagcacctacttaagtagctatagcatgaactgggtccgcca gcctggtaccaacagaaacctggccaggctcggctccagggaaggggctggagtgggtct ccaggctcgtcatctatgatgcatccaacaggcatacattagtggcattaatagtgccatata gccactggcatcccagccaggttcagtggcggttacgcagactctgtgaagggccgcttca tgggtctgggacagacttcactctcaccatcagccatctccagagacaacgccaagaactc cagcctagagcctgaagattttgcagtttattacactgtatctgcaaatgaacagcctgagag tgtcaacagcgtctcaactggcctctcactttcgtcgaggacacggctgtgtattactgtgcg gcggagggaccaaagtggatatcaaacagagataaatacttaggtataaaagatatg tggggccaagggacaatggtcaccgtctct tcagBeta38 gaggtgcagctggtacagtctggagcaga 541cagtctgtgttgacgcagccaccctcagcgtctg 543 ggtgaaaaagccgggggagtctctgaagaggacccccgggcagagggtcaccatctcttgttc tctcctgtaagggctctggatacagctttacctggaagcagctccaacctcggaggtaatactgta aactactggatcggctgggtgcgccagatgaactggtaccagcagctcccaggaacggcccc cccgggaaaggcctggagtggatggggatcaaactcctcatctatagtaataatcagcggccctc catctatcctggtgactctggtaccagatacaggggtccctgaccgattctctggctccaagtct agcccgtccttccaaggccaggtcaccatcggcacctcagcctccctggccatcagtgggctc tcagccgacaagtccatcagaaccgcctaccagtctgaggatgaggctgattattactgtgcagc ctgcagtggagcagcctgaaggcctcggaatgggatgacagcctgaatggtcccgtcttcgg cagcgccatgtattactgtgcgaggtctagaaactgggaccaaggtcaccgtcctag gtgggagctactgggggctattatgactactatatggacgtctggggccaagggaccacgg tcaccgtctcctca Beta40caggtgcagctggtggagtcgggcccag 551 cagtctgtgttgactcagccaccctcggtgtca 553gacaggtgaagccttcggagaccctgtccc gtgtccccaggacagacggcccggatcaccttcacctgcactgtctctggtggctccatcag gctctggagatgcattgtcaacgcaaaatggtcagtagtagttactactggggctggatccgc aattggtaccagcagaagccaggccaggcccagcccccagggaagggactggagtggat cctgtgatggtgatatgtaaagacagtgagagtgggagtatctattatagtgggagcgcctac gccctcagggatccctgagcgattctctggcttataacccgtccctcaagagtcgagtcacca ccaggtcagggacaacagtcacgttgaccattatccgtagacacgtccaagaaccagttctc cagtggagtccaggcagaagacgaagctgacctgaagctgaactctgtgaccgccgcaga ctatcactgtcaatcagcagacaacagggcaccacggctgtcttttactgtgcgagacacgca atgtagtattcggcggagggaccaagctgacgctcccagtccgggggacaactggttcga cgtcctag cccctggggccagggaaccctggtcaccgtctcctcag Beta43 gaggtgcagctggtggagtctgggggag 561tcctatgagctgactcagccaccctcagtgtca 563 gcgtggtccagcctgggaggtccctgagagtggccccaggaaagacggccacgattacct ctctcctgtgcagcgtctggattcacctttaggtgggggaaacaacattggaactaaaagtgtg tagttatggcatgcactgggtccgccaggccactggtaccagcagaagccaggccaggccc tccaggcaaggggctggagtgggtggcactgtgttggtcatctattataatagcgaccggcc gttatatggtatgatggaagtaataacttctatctccgggatccctgagcgattctctggctccaa gcagactccgtgaagggccgattcaccatcctctgggaacacggtcaccctgaccatcagca tccagagacaatttcaagaacacgctgtatttgggtcgaagccggggatgaggccgactatta gcaaatgaacagcctgagagccgaggacctgtcaggtgtgggatagtggtagtgatcattat acggctgtgtattactgtgcgagatcatattggtcttcggaactgggaccaaggtcaccgtcgt tagtggtggtttctgcttcggctactactatg aggtttggacgtgtggggccaagggaccacgg tcaccgtctcctca Beta44caggtgcagctggtgcagtctggagctga 571 cagtctgtcgtgacgcagcctgcctccgtgtctg 573ggtgaagaagcctggggcctcagtgaag ggtctcctggacagtcgatcaccatctcctgcacgtctcctgcaaggcttctggttacaccttta tggaaccagcagtgatgttgggagttataaccttccagctatggtatcagctgggtgcgacag gtctcctggtaccaacagcacccaggcaaagcgcccctggacaagggcttgagtggatgg ccccaaactcatgatttatgcgggcagtaagcggatggatcagcccttacaatggtaacaca gccctcaggggtttctaatcgcttctctggctccacactatgcacagaagctccagggcagag agtctggcaacacggcctccctgacaatctctggtcaccatgaccacagacacatccacgagc gctccaggctgaggacgaggctgattattactgacagcctacatggagctgaggagcctga ctgctcatatgcaggtagtagcacttgggtgttcgatctgacgacacggccgtatattactgtg ggcggagggaccaagctgaccgtcctagcgagagatggggagttattgggctggttc gacccctggggccagggaaccctggtca ccgtctcctcagBeta45 ccaggtcagctggtggaatctgggggaa 581gccatccagttgacccagtctccatcctccctg 583 gcttggtacagcctgggggggccctgagtctgcatctgtaggagacagagtcaccatcact actctcctgtgaagcctctggattcaccttttgccaggcgagtcaggacattaggaactattt agcgactatgccatgagctgggtccgccaaaattggtatcagcagaaaccagggaaagcc ggctccagggaaggggctggagtgggtcctaagctcctgatctacgatgcatccaatttgg ctcagttattaatagtagtggtggtatcacaaaacaggggtcccatcaaggttcagtggaagt aactacgcagactccgtgaagggccggttggatctgggacagattttactttcaccatcggca caccatctccagaaacaattccaagaacagcctgcagcctgaagatattgcaacatattact cgctctatctgcaaatgaacagcctgagagtcaacaatatgataatctccgggccactttcg ggcgacgacacggccatatattactgtgcgcggagggaccaaggtggagatcaaac gaagggacccccgagaattaacaccttctacaggcactactacggtatggacgtctgg ggccaagggatcacggtcaccgtctcctc a Beta47caggtgcagctggtggagtctgggcctg 591 gaaattgtgttgacgcagtctccaggcaccct 593aaatgaagaagcctgggacctcagtgaa gtctttgtctccaggggaaagagccaccctctcggtctcctgcaaggcttctggattcaccttt ctgcagggccagtcagagtgttagcagaaactattacgtctgctgttcagtgggtgcgacagg acttagcctggtaccagcagaaacctggccactcgtggacaacgccttgagtggatggga ggttcccaggctcctcatctatggtgcatccagtggatcgccgttggcagtggtaacacaaa cagggccactggcatcccagacaggttcagactacgcacagaaattccaggacagagtc ggtagtgggtctgggacagacttcactctcacaccattaacagggacatgtccacaagcac catcaacagactggagtctgaagattttgcagtagcctacatggagctgagcagcctgaga gtattactgtcagcagtatggtagctccctattctccgaggacacggccgtgtattactgtgc actttcggccctgggaccaaagtggatatcaaggccccgcattgtaatcgtaccagctgcc ac atgatggttttgatatctggggccaagggacaatggtcaccgtctcttcag Beta48 gaagtgcagctggtggagtcgggggga 601gccatccagatgacccagtctcttcctcctgcg 603 ggcctggtcaagcctggggagtccctgagactctggctccaggggaaagagccaccctct actctcctgtgcagcctctggattcaccttccctgcagggccagtcagagtgttagcaacaa agtagctatgccatgaactgggtccgccacttagcctggtaccagcagaaacctggccag ggctccagggaaggggctggagtgggtgctcccaggctcctcatctatggtgcatccacc ctcatccattagtactggtagttatttcatataagggccactggtatcccagccaggttcagtgg ctactcagactcagtgaagggccgattcacagtgggtctgggacagagttcactctcaccatc ccatttccagagacaacgccaagaactcaagcagcctgcagtctgaagattttgcagtttatt ctgtatctgcaaatgaacagcctgagagcactgtcagcagtataataactggcctccgtgg cgcggacacggctatctattactgtgcgaacgttcggccaagggaccaaagtggatatca gaggaaaggaagatacaagcgctgctttt aacgatatctggggccaagggacaatggtca ccgtctcttcag Beta49gaggtgcagctggtgcagtctggggctg 611 gccatccggatgacccagtctccaggcaccct 613aggtgaagaagcctgggtcctcggtgaa gtctttgtctccaggggaaagagccaccctctcggtctcctgcaaggcttctggaggcacctt ctgcagggccagtcagagtgttagcagcagctacagcagctctgttatcagctgggtgcgac cttagcctggtaccagcagaaacctggccaggaggcccctggacaaggccttgagtggat ctcccaggctcctcatctatggtgcatccagcaggggagggatcatccctctctttggttcagc ggccactggcatcccagacaggttcagtggcaaactacgcacagaagttccagggcaga agtgggtctgggacagacttcactctcaccatcgtcacgattaccgcggacgaatccacga agcagactggagcctgaagattttgcagtgtatgcacagcctacatggagatgactagcctg tactgtcagcagtatggtacctcaccttcgtggagatctgaagacacggccgtgtattactgt acgttcggccaagggaccaaggtggagatcagcgaaagtttcccagtgggcgttaatactc aac ttctggggccagggaaccctggtcaccgtctcctcag Beta50 gaggtgcagctggtgcagtctggggctg 621gatattgtgatgactcagtctccaggcaccctg 623 aggtgaagaagcctgggtcctcggtgaatctttgtctccaggggaaagagccaccctctcc ggtctcctgcaaggcgtctagaggcacctttgcagggccagtcagagttttaccagcagcta caacacctatgttttcacctgggtgcgacacttagcctggtaccagcagaaacctggccagg ggcccctggacaagggcttgagtggatgctcccaggctcctcatctatggtgcatccagca ggagggatcatccctttctttggtacagcagggccactggcatcccagacaggttcagtgg gactacgcacagaagttccagggcagagcactgggtctgggacagacttcactctcaccat tcacgattaccgcggacgactccacgagcagcagactggagcctgaagattttgcagtata cacagcctacatggagctgagcagcctgttactgtcagcagtatggtacgtcacctcgcat agatctgaggacacggccgtgtattactgtgtacacttttggccaggggaccaaagtggatat tcgaggctcagccagtgggacctactacc caaaccatgtggggccagggaaccctggtcacc gtctcctcag Beta51cagctgcagctggtggagtctggggctga 631 gccatccggatgacccagtctccatcctcactg 633ggtgaagaagcctggggcttcagtgaagg tctgcatctgtaggagacagagtcaccatcacttctcctgcaaggtttccggatacaccctcact tgtcgggcgagtcagggcattaggaattatttagaattatccatgcactgggtgcgacaggct gcctggtttcagcagaaaccagggaaagccccctggaaaagggcttgagtggatgggggg ctaagtccctgatctatgctgcatccagtttgcattttgatcctgaagatggtgagacaatctac aagtggggtcccatcaaagttcagcggcagtggcacagaagttccagggcagagtcaccat gatctgggacagatttcactctcaccatcagcagaccgaggacacatctatagacacagtgta gcctgcagcctgaagattttgcaacttattactgcatggagctgagcagcctgagatctgagg ccaacagtataatagttaccccctcaccttcggacacggccgtgtattactgtgcaatagatcg ccaagggacacgactggagattaaaccaagcactggctggtaggtcttgactactgg ggccagggaaccctggtcaccgtctcctca g Beta53caggtgcagctggtgcagtccggagcag 641 gacatccagatgacccagtctccagccaccct 643aggtgaaaaagcccggggagtctctgag gtctgtgtctccaggggaaagagccaccctctgatctcctgtaagggttctggacacaactc cctgcagggccagtcaaagtgttagcagcactcccagctactggattagctgggtgcgcca cttagcctggtaccagcagaaacctggccaggatgcccgggaaaggcctggagtggatg gctcccaggctcctcatctatggtgcatccaccgggagaattgatcctagtgactcttatacc agggccactggtatcccagccaggttcagtggaactacagcccgtccttccaaggccatgtc cagtgggtctgggacagagttcactctcaccatcaccatctcagctgacaagtccatcagtact agcagcctgcagtctgaagattttgcagtttattgcctacctacagtggagcagcctgcagg actgtcagcaatataataactggtccacgtggacctcggacaccgccatttattactgtgcga cgttcggccaagggaccaaagtggatatcaagacacgtggttgcattgactcatttgtaccc ac tgactactggggccagggaaccctggtcaccgtctcctcag Beta54 caggtgcagctgcaggagtcgggcccag 651gacatccagttgacccagtctccatccttcctgt 653 gactggtgaagccttcggagaccctgtccctgcatctgtaggagacagagtcaccatcactt ctcacctgcactgtctttggtggctccatcagccgggccagtcagggcattagcagttattta ccagtagtaatcactactgggtctggatccgcctggtatcagcaaaaacctgggaaagccc gccagcccccagggaaggggctggagtctaagctcctgatctatgctgcatccactttgca ggattgggagtatgtattatagtgggagcaaagtggggtcccatcaaggttcagcggcagt ccgcctacaacccgtccctcacgaatcgaggatctgggacagaattcactctcacaatcag gtcaccatatccgtagacacgtccaagaacagcctgcagcctgaagattttgcaacttattac ccagttctccctgaagctgagctccgtgactgtcaacagcttaatagttacccgctcactttcg cgccgcagacacggctgtgtattactgtggcggagggaccaaggtggaaatcaaac cgagacaaatcgggcccaagaggccctcgcaagtggctgactggttcgacccctggg gccagggaaccctggtcaccgtctcctca g Beta55caggtgcagctgcaggagtcgggccca 661 gccatccggatgacccagtctccttccaccct 663ggactggtgaagccttcggagaccctgtc gtctgcatctgtaggagacagagtcaccatcgcctcacttgcactgtctctggtgactccatc cttgccgggccagtcagagtattagtgcctggtagcagtagtcgttactactggggctggatc tggcctggtatcagcagaaaccagggaaagccgccagcccccagggaaggggctggag ccctaagctcctgatctataaggcatctagtttatggattgggactttctattatagtgggatca gaaagtggggtcccatcaaggttcagcggcacgtactacaacc gtggatctgggaca cgtccctcaagagtcgagtcaccatattcgtgaattcactctcaccatcaacagcctgcagcct agacacgtccaagaaccagttctccctgaagatgattttgccacttattactgccaacagtatat gctgagctctgtgaccgccgcagacacggtagttcttctccgtggacgttcggccaagggac ctgtttattactgtgcgagaccccgaccccccaaggtggaaatcaaac cgattactatgataatagtggtgcgctcctttttgatatctggggccaagggacaatggtcac cgtctcttcag Beta56cagctgcagctgcaggagtcgggcccag 671 caatctgccctgactcagcctgcctccgtgtct 673gactggtgaggccttcacagaccctgtccc gggtctcctggacagtcgatcaccatctcctgctctcctgcactgtctctggtggctccatcagc actggaaccagcagtgacgttagtggctataaagtgccactcactactggagctggatccgc ctatgtctcctggtaccaacaacacccagacaacagcacccagggagaggcctggagtgga agcccccaaactcttgatttatgatgtcactaatcttgggtacatctattacactgggggcaccttt ggcccacaggggtttctaatcgcttctctgccttacaatccgtccctcaagagtcgacttaccata ccaagtctggcaacacggcctccctgaccatctcagtggacacgtctaagaaccagttctccc tctgggctccaggctgaggacgaggctgattatgaagctgagcgctgtgactgccgcggac ttactgcagctcagatacaaatagtattcctcggacggccgtgtattactgtgcgagagttatag tatgtggtgttcggcggagggaccaagctgaccagctcgtccgggatctacctactttgacttct cgtcctag ggggccggggaaccctggtcaccgtctcctcag

Amino Acid Sequences of CDRs

Heavy chain CDR SEQ SEQ SEQ Ab ID ID ID number CDR1-IMGT NO CDR2-IMGTNO. CDR3-IMGT NO. Beta 6 GGSISSSSH 405 IYYSESA 406 ARVTEPRWTSCY 407 YFDY Beta 10 GGSISSSSY 415 IYYSGST 416 ARERSAPLAGNW 417 Y FDP Beta 20GFPFSNYG 425 IWYDGSNK 426 AKDGYTAHYYY 427 YYMDV Beta 22 GFTFSNYG 435ISYDGSHK 436 AKDSSAAIPYYYY 437 GMDV Beta 23 GGSISSSSY 445 VYYSGGT 446ARIWFGEPAGGY 447 Y FDY Beta 24 DGSISSSDY 455 IYYTGST 456 ARLVVPSPKGSW457 Y FDP Beta 25 GFTFTSSA 465 IVVGSGNT 466 AAVYCSGGSCND 467 AFDIBeta 26 GASISNYY 475 IYYTGST 476 ARAYCSGGSCFD 477 TFDI Beta 27 GLTVRSNY485 IYSGGST 486 ARDLVVYGMDV 487 Beta 29 GFTFSNYG 495 ISYEESNR 496AKDQGPATVMVT 497 AIRGAMDV Beta 30 GYTFTDYY 505 INSKDGGA 506ARSASTVTEPPTN 507 WFDP Beta 32 GYTFTGYY 515 INPNSGGT 516 ARVGAHDYYDSS517 DNWFDP Beta 33 GYPLTGYY 525 LNPNSGGT 526 ARDGGGIDDYVQ 527 EDGMDVBeta 34 GFTFSSYS 535 ISGINSAI 536 ARDKYLGIKDM 537 Beta 38 GYSFTNYW 545IYPGDSGT 546 ARSRVGATGGYY 547 DYYMDV Beta 40 GGSISSSSY 555 IYYSGSA 556ARHAAPSPGDNW 557 Y FDP Beta 43 GFTFSSYG 565 IWYDGSNN 566 ARSYCSGGFCFG567 YYYGLDV Beta 44 GYTFTSYG 575 ISPYNGNT 576 ARDGELLGWFDP 577 Beta 45GFTFSDYA 585 INSSGGIT 586 AKGPPRINTFYRH 587 YYGMDV Beta 47 GFTFITSA 595IAVGSGNT 596 AAPHCNRTSCHD 597 GFDI Beta 48 GFTFSSYA 605 ISTGSYFI 606ARGKEDTSAAFDI 607 Beta 49 GGTFSSSV 615 IIPLFGSA 616 AKVSQWALILF 617Beta 50 RGTFNTYV 625 IIPFFGTA 626 SRLSQWDLLPM 627 Beta 51 GYTLTELS 635FDPEDGET 636 AIDRKHWLVGLD 637 Y Beta 53 GHNSPSYW 645 IDPSDSYT 646ARHVVALTHLYP 647 DY Beta 54 GGSITSSNH 655 MYYSGST 656 ARQIGPKRPSQVA 657Y DWFDP Beta 55 GDSISSSRY 665 FYYSGIT 666 ARPRPPDYYDNS 667 Y GALLFDIBeta 56 GGSISSATH 675 IYYTGGT 676 ARVIAARPGSTYF 677 Y DF

Light Chain CDR SEQ SEQ SEQ Ab ID ID ID number CDR1-IMGT NO. CDR2-IMGTNO. CDR3-IMGT NO. Beta 6 QSVTSY 408 DAS 409 QLRSNWPPIT 410 Beta 10QGISSY 418 AAS 419 QQLNTYPSIT 420 Beta 20 QSVSSSY 428 GAS 429 QQYGSSPGIT430 Beta 22 QSILYNSNNKTY 438 WAS 439 QQYYSIPLI 440 Beta 23 KLGDKN 448EYN 449 QAWDTGTHV 450 Beta 24 SIDVGNYNL 458 EGS 459 CSYVGSSTYV 460Beta 25 QSVSSSY 468 GAS 469 QQYGSSPFT 470 Beta 26 NIGSKS 478 DDS 479QVWDSASDSGV 480 Beta 27 QSVSSSS 488 GTS 489 QQYGSSPL 490 Beta 29QSVLYSSNNKNY 498 WAS 499 QQYFGSPSIT 500 Beta 30 QGIRND 508 AAS 509LQHNSYLRFT 510 Beta 32 QGISSW 518 AAS 519 QQANSFPWT 520 Beta 33 ALSKQH528 KDS 529 QSADNSGSRYV 530 Beta 34 QSVSTY 538 DAS 539 QQRLNWPLT 540Beta 38 SSNLGGNT 548 SNN 549 AAWDDSLNGPV 550 Beta 40 ALSTQN 558 KDS 559QSADNRAHVV 560 Beta 43 NIGTKS 568 YNS 569 QVWDSGSDHYV 570 Beta 44SSDVGSYNL 578 AGS 579 CSYAGSSTWV 580 Beta 45 QDIRNY 588 DAS 589QQYDNLRAT 590 Beta 47 QSVSRNY 598 GAS 599 QQYGSSLFT 600 Beta 48 QSVSNN608 GAS 609 QQYNNWPPWT 610 Beta 49 QSVSSSY 618 GAS 619 QQYGTSPSWT 620Beta 50 QSFTSSY 628 GAS 629 QQYGTSPRMYT 630 Beta 51 QGIRNY 638 AAS 639QQYNSYPLT 640 Beta 53 QSVSST 648 GAS 649 QQYNNWSTWT 650 Beta 54 QGISSY658 AAS 659 QQLNSYPLT 660 Beta 55 QSISAW 668 KAS 669 QQYISSSPWT 670Beta 56 SSDVSGYNY 678 DVT 679 SSDINSIPR 680

Amino Acid Sequence of Heavy Chain and Light Chain Variable Regions ofSelected Antibodies

Heavy chain Light chain SEQ SEQ Antibody ID ID number:Amino acid sequence NO: Amino acid sequence NO: Omi02 EVQLVESGAEVKKPGSS682 VIWMTQSPGTLSLSPGER 684 VKVSCKASGGTFSSYAI ATLSCRASQSVSSTYLANWVRQAPGQGLEWMG WYQQKPGQAPRLLIYGA GIIPIFRTPHYAQKFQGR SSRATGIPDRFSGSGSGTVTITADESTGTAYMELSS DFTLTISRLEPEDFAVYY LRSEDTAVYYCASPSCGCQHYGSSPLTFGQGTRLE GDCPQYLKSSKLDWYF IK DLWGRGTLVTVSS Omi03EVQLVESGGGLIQPGGS 692 EIVLTQSPGTLSLSPGERA 694 LRLSCAASEIIVSRNYMSTLSCRASQSVSSSYLAWY WVRQAPGKGLEWVSVI QQKPGQAPRLLIYGASSRYSGGSTFYADSVKGRFTI ATGIPDRFSGSGSGTDFT SRDNSKNTLYLQMNSLRLTISRLEPEDFAVYYCQQ AEDTAVYYCARDLDVV YGSSPGYTFGQGTKVDIK GGTDYWGQGTLVTVSSOmi06 EVQLLESGPGLVKPSETL 702 AIRMTQSPSSLAASVGDR 704 SLTCTVSGGSISRYSWSVTISCRAGQSISSFLHWY WIRQPAGRGLEWIGRM QQKVGKAPKLLIYDASSL YSSGGTNYNPSLESRVTQSGVPSRFSGSGSGTDFT MSLDTSKKQFSLKLSSV LTISSLQPEDFAAYYCQQTAADTAVYYCAAASIDQ SYENPLTFGGGTKVDIK VWGTYRDAFDIWGQGT MVTVSS Omi08EVQLVESGAEVKRPGASV 712 QSVVTQPPSVSGAPGQRVT 714 KVSCKASGYTFTNYFMHWVISCTGSSSNIGAGYDVHWY RQAPGQGLEWMGVINPSD QQLPGAAPKLLIYGNTNRPGGASYPQKFQGRVTMTRD SGVPDRFSGSKSGTSASLAIT TSTSTVYMDLSSLRSEDTAGLQAEDEADYYCQSYDITL VYSCARGAFDVSGSWYVP SGSGYVFGTGTKVTVL FDYWGQGTLVTVSSOmi09 QVQLVESGGGVVQPGRSL 722 SYELTQPPSVSVSPGQTARIT 724RLSCAASGFTFRTYAVHW CSGDALPKQYTYWYQQKPG VRQAPGKGPEWVAVISYDQPPVLVIYKDSERPSGIPERF GSNKYYADSVKGRFTLSR SGSSSGTTVTLTISGVQAEDEDTSKNTLYLQMNSLRAED ADYYCQSTDSSATYPGNVVF TAVYYCASRGDTVTTGDA GGGTKLTVLFDIWGQGTMVTVSS Omi12 EVQLVESGPEVKKPGTSVK 732 AIRMTQSPGTLSLSPGERATL 734VSCKASGFSFSMSAMQWV SCRASQSVRSSYLAWYQQKP RRARGQRLEWIGWIVPGSGQAPRLLIYGASTRATGIPDR GNANYAQKFQERVTITRDE FSGSGSGTDFILTINRLEPEDLSTNTGYMELSSLRSEDTAVY AVYYCQQFGSSPWTFGQGT YCAAPHCNKTNCYDAFDI KVDIKWGQGTMVTVSS Omi16 EVQLVESGGGVVQPGGSL 742 DVVMTQSPGTLALSPGERA 744RLSCAASGIIVSANYMTWV TLSCRTSQSVSSNYLAWYQ RQAPGKGLEWVSVIYPGGQKPGQAPRLLIYGASSRAT STFYADSVKGRFTISRDNS GIPDRFSGSGSGTDFTLTISKNTLYLQMNSLRVEDSAV RLEPEDFAVYYCQQFGSSP YYCARDLELAGENDFWGQ RYTFGQGTKVEIKGTLVTVSS Omi17 QVQLVESGGGVVQPGGSLR 752 DIVMTQSPGTLSLSPGERATL 754LSCAASGVTVSSNYMSWVR SCRASQGVSSIYLAWYQQKP QAPGKGLEWVSVLYAGGSTGQAPRLVLYGASSRATGIPD FYADSVKGRFTISRDNSKNT RFSGSGSGTDFTLTISRLEPELYLQMNSLRAEDTAAYYC DFAVYYCQQYGSSPRYTFG ARDLAVAGFLDSWGQGTL QGTKVEIK VTVSSOmi18 QVQLVESGGGLIQPGGSLR 762 SYELTQPPSVSVAPGQTARI 764LSCAASGITVSSNYMTWV TCGGNNDGAKSVHWYQQK RQAPGKGLEWVSLLYAGGPGQAPVLVVYDDSDRPSGI SAFYADSVKGRFTISRDNS PERFSGSNSGNTATLTITRIEKNTLYLLMNSLRVGDTAV AGDEADYYCQVWDSSRDH YYCARDLQVYGMDVWGQ VFGTGTKVTVLGTTVTVSS Omi20 EVQLVESGGGLVQPGGSLR 772 AIQMTQSPSFLSASVGDRV 774LSCEASEITVSSNYMNWVRQ TITCRASQGISGDLAWYQQ APGKGLEWVSVLFAGGTTYKPGKAPKLLIYAASTLQSG YADSVKGRFTISRDNSKNTL VPSRFSGSGSGTEFTLTISSLYLQMNTLRIEDTAIYYCARD QPEDFATYYCQHLNSYPLT LVAYGVDVWGQGTTVTVS FGGGTKVEIK SOmi23 QVQLQESGPGLVKSSQTLS 782 AIQMTQSPSSLSASVGDRVT 784LTCTVSGDSISRGGYYWS ITCRASQAISNSLAWYQQK WIRQHPGKGLEWIGSIYYSPGKAPKLLLYAASTLESGV GSTYYNPSLKSRFTISVDTS PSRFSGSGSGTDFTLTISSLQKNQFSLKLSSVTAADTAV PEDFATYFCQQYYSTPPRTF YHCAREIGFLDYWGQGTL GQGTKVDIKVTVSS Omi24 QVQLVESGAEVKKPGSSVK 792 RHWMTQSPATLSVSPGERAT 794VSCKASGGTFSSHGVIWVR LSCRASQSIGSNLAWYQQKP QAPGQGLEWMGGIIPIFPTAGQAPRLLIYGAATRATGIPA NYAQKFQGRVTITADKPSNT RFSGSGSGTEFTLTISSLQSEDAYMELSSLRSEDTAVYYCA FAVYYCQQYNDWPPRTFGQ RARGEHDSVWGSFHYYFD GTKVEIKYWGQGTLVTVSS Omi25 QVQLVESGGGLVQPGRSLR 802 AIQMTQSPSSLSASVGDRV 804LSCAASGFTFDDYAMHWVR TITCRTSQTISSYLNWYQQK QVPGKGLEWVSGISWNSGSIPGKAPKLLIYDASSLQSGVP VYADFVKGRFTIARDNAKN SRFSGSGYGTDFTLTISSLQSLFLQMNSLRAEDTALYYC PEDFATYFCQQSYNTPYAF AKSTALRHQYYYGMDVWG GQGTKVEIKQGTTVTVSS Omi26 QVQLVQSGTEVKKPGASV 812 QSVVTQPPSVSEAPRQRVTI 814KVSCKASDYTFTRFGIIWV SCSGSNSNIGNNAVNWYQ RQAPGQGLEWMGQINPYNQLPGKAPKLLVYYDDLLPS GNTDYAQKFQGRVTLTTD GVSDRFSGSKSGTSASLAISTSTNTAYMELRSLRSDDTA GLQSEDKADYYCAAWDDS VYYCARSAGSPTGLDYWGLNALVFGGGTKLTVL QGTLVTVSS Omi27 EVQLLESGGGLVQPGGSLR 822EIVMTQSPSSLSASVGDRVT 824 LSCVASGLTVSSNYMSWV ITCRASQGIGNDLGWYQQKRQAPGKGLEWVSIIYPGGT PGKAPKVLIYAASNLQSGV TYYADSVKGRFTTSRDKSPSRFSGSGSGTDFTLTISSLQ KNTLYLQMNSLRAEDTAV PEDFATYYCLQDSNYPYTFYYCARDLAVAGGMDVWG GQGTKVEIK QGTTVTVSS Omi28 EVQLVESGGGLVQPGGSLR 832DVVMTQSPGTLSLSPGERA 834 LSCAASGVIVSSNYMSWVR TLSCRASQFIGSSYLAWYQQAPGKGLQWVSVIYSGGST QKPGQAPRLLIYGASNRAT FYADSVKGRFTISRDNSKNTGVPDRFSGSGSGTDFTLTIS LYLQMNSLRAEDTAVYYC RLEPEDFAVYYCQQYGSAPARDLLEAGGTDYWGQGTL GTFGQGTKVEIK VTVSS Omi29 QVQLVESGGGLVQPGGSL 842NFMLTQPASVSGSPGQSITI 844 RLSCAASGLIVSRNYMSW SCTGTSSDVGGYNYVSWYVRQAPGKGLEWVSLIYAG QQHPGKAPKLMIYDVSNRP GSTFYSDSVKGRFTISRHSSSGVSNRFSGSNSGNTASLTI ENTLFLQMNSLRAEDTAV SGLQAEDEADYYCSSYTSGYYCARDLVHYGMDVWGQ STWVFGGGTKLTVL GTTVTVSS Omi30 EVQLVESGAEVKKPGSSV 852QSVLTQPPSASGTPGQRVTI 854 KVSCKASGGTFSRYAISW SCSGSSSNIGGDIVNWYLQLVRQAPGQGLEWMGGIIPIF PGTAPKLLIYSNNQRPSGVP DATNYAQKFHDRVTITADDRFSGSRSGTSASLAISGLQS KSASTAYMELSSLRSDDTA EDEGYYYCAAWDDSLNGQVYYCARERTYCSGGTCYG VFGGGTKLTVL GYFYYGMDVWGQGTTVT VSS Omi31EVQLVQSGAEVKKPGSSVK 862 QSVVTQPPSASGTPGQRVTI 864 VSCKASGGTFSSYGISWVRSCSGSSSDIGSNTVNWYQQ QAPGLGLEWMGGVIPILSAK LPGTAPKLLIYTNNQRPSGVHYAQRFQGRVTITADKSTGT PDRFSGSKSGTSASLAITGL AYMELSSLRSEDTAVYYCAQSEDEADYFCAAWDESLN RDILHHDDLWGRFYYDGM GRVFGGGTKLTVL DVWGQGTTVTVSS Omi32EVQLVESGG.GVVQPGRSL 872 AIRMTQSPGTLSLSPGERAT 874 RLSCAASGFTFSNYGMHWLSCRASQSISSSFLAWYQQ VRQAPGKGLEWVAVYWY KPGQAPRLLIYGASSRATGIDGGNKFYADSVK.GRFTIS PDRFSGSGSGTDFTLTISRL RDNSKNTLYLQMNSLRVEEPEDFAVYYCQQYGTSPRL DTAVYYCARDTAPPDYW TFGGGTKVDIK GQGTLVTVSS Omi33EVQLLESGGGVVQPGRSL 882 EIVLTQSPGTLSLSPGERATL 884 RLSCAASGFKFSDYGMHWSCRASQSISSNFLAWYQQKP VRQAPGKGLEWVAVYWY GQAPRLLIYGASSRATGIPDRFDGGTKFYADSVKGRFTISR SGSGSGTDFTLTISRLEPEDF DNSKNTLYLQMSSLRVEDAVYYCQQYGTSPRLTFGGGT TAVYYCARDTAPPDYWG KVDIK QGTLVTVSS Omi34QVQLVQSGAEVKKPGSSV 892 QSVLTQPPSVSGAPGQRVTIS 894 KVSCKASGGTFSSYGIRWCTGSSSNIGADYDVHWYQQ VRQAPGQGLEWMGGIIPV LPGAAPKLLIYGNNNRPSGVFGATNYAQKFQDRVTITA PDRFSGSKSGTSASLAITGLQ DKSTATAYMELSSLKSDDAEDEADYYCQSYDSSQNAF TAVYFCARDALSASGWTG YVFGTGTKVTVL PFDSWGQGTLVTVSSOmi35 QVQLVESGGGLVQPGRSLR 902 QSVVTQPPSVSVAPGQTARIT 904LSCAASGFTFDDYAMHWV CGGTNIGSKSVHWYQQKPGQ RQAPGKGLEWVSGSTWNSAPVLVVYDDSDRPSGIPERFS GTIDYADSVKGRFTISRDN GSNSGNTATLTITWVEAGDEAKNSLYLQMNSLRAEDTA ADYYCQVWDSSSDNVLFGG LYYCAKDRFRKGCSSTGC GTKLTVLYKENYGMDVWGQGTTVT VSS Omi36 EVQLVESGGGVVQPGGSL 912 DIVMTQSPGTLSLSPGERATL914 RLSCAASGIIVSANYMTWV SCRTSQSVSSNYLAWYQQKP RQAPGKGLEWVSVIYPGGGQAPRLLIYGASSRATGIPDR STFYADSVKGRFTISRDNS FSGSGSGTDFTLTISRLEPEDFKNTLYLQMNSLRVEDSAV AVYYCQQFGSSPRYTFGQGT YYCARDLELAGENDYWG KVEIKQGTLVTVSS Omi38 QVQLVESGAEVKKPGSSV 922 AIRMTQSPSTLSASVGDRVT 924KVSCKASGGNFNMYTISW ITCRASQTINSWLAWYQQK VRQAPGRGLEWMGRFIPIAPGKAPKLLIYDASNLESGVP NKANYAQNFPGRVTITAD SRFSGSGSGTEFTLTISSLQPDKSTSTVYMELRSLTSDDTA DFATYYCQQYESYSPITFGQ VYYCARSGSYDAFDVWG GTRLEIKQGTMVTVSS Omi39 QVQLVESGGVVVQPGGSL 932 EIVLTQSPDSLAVSLGERAT 934RLSCAASGFSFDDYSMHW INCKSSQNVLYSSNNKNYL VRQAPGKGLEWVSVIYWDAWYQQKPGQPPQLLIYWA GVSKYYADSVKGRFTISRD STRESGVPDRFSGSGSGTDFNSKNSLYLQMNSLRTEDT TLTISSLQAEDVAVYYCHQ AVYYCAKDSEDCSSTSCYYYSTPFTFGPGTKVDIK MDVWGKGTTVTVSS Omi41 QVQLVQSGAEVKKPGASV 942AIQMTQSPDSLAVSLGERA 944 KVSCKAAGYSFMNYGINW TINCKSSQSVLYSSNNKNYLVRQAPGQGLEWMGWINT AWYQQKPGQPPKLVIYWA YNGNAKYAQKFQGRVTMSTRESGVPDRFSGSGSGTDF TTDTSTSTAYMELRSLRSG TLTISSLQAEDVAVYYCHQDTAVYYCARDPFTGYDDV YYSSPRTFGQGTKVEIK WGGDYWGQGTLVTVSS Omi42EVQLLETGGGLVQPGRSLR 952 QSVVTQPPSASGSLGQSVTI 954 LSCAASGFPFDDYAIHWVRSCTGTSSDVGGYNYVSWY LAPGKGLEWVSSISWDSGSI QQHPGKAPKLMIFEVSKRPGYADSVKGRFTISRDNAKN SGVPDRFSGSKSGNTASLT SLYLQMNSLRAEDTALYYCVSGLQAEDEADYYCSSYA AKGAFPGYSSGWYYGLDV GNKGVFGGGTKLTVL WGQGATVTVSS

Nucleotide Sequence of Heavy Chain and Light Chain Variable Regions ofSelected Antibodies

SEQ SEQ Antibody Heavy chain ID Light chain ID number:Nucleotide Sequence NO: Nucleotide sequence NO: Omi02gaggtgcagctggtggagtctggggctga 681 gtcatctggatgacccagtctccaggcaccct 683ggtgaagaagcctgggtcctcggtgaagg gtctttgtctccaggggaaagagccaccctctctctcctgcaaggcttctggaggcaccttcag ctgcagggccagtcagagtgttagcagcacctacagctatgctatcaactgggtgcgacaggc cttagcctggtaccagcagaaacctggccaggccctggacaagggcttgagtggatgggag ctcccaggctcctcatctatggtgcatccagcagggatcatccctatctttcgtacgccgcactac ggccactggcatcccagacaggttcagtggcgcacagaaattccagggcagagtcacgatt agtgggtctgggacagacttcactctcaccatcaccgcggacgaatctacgggcacagccta agcagactggaacctgaagattttgcagtgtatcatggagctgagcagcctgcgatctgaag tactgtcagcactatggtagctcacctctcacctacacggccgtgtattactgtgcgagcccct tcggccaagggacacgactggagattaaaccttgtggtggtgactgcccccagtacttaaa atcatccaaactagactggtacttcgatctctggggccgtggcaccctggtcaccgtctcct cag Omi03 gaggtgcagctggtggagtctggaggaggc691 gaaattgtgttgacacagtctccaggcaccctg 693ttgatccagcctggggggtccctgagactct tctttgtctccaggggaaagagccaccctctcccctgtgcagcctctgagatcatcgtcagtagg tgcagggccagtcagagtgttagcagcagctaaactacatgagctgggtccgccaggctcca cttagcctggtaccagcagaaacctggccaggggaaggggctggagtgggtctcagttatt gctcccaggctcctcatctatggtgcatccagctatagcggtggtagcacgttctacgcagact agggccactggcatcccagacaggttcagtgccgtgaagggccgattcaccatctccagag gcagtgggtctgggacagacttcactctcaccacaattccaagaacacgctgtatcttcaaatga atcagcagactggagcctgaagattttgcagtacagcctgagagccgaggacacggccgtg gtattactgtcagcagtatggtagctcaccaggtattactgtgcgagagacctcgacgtagtgg gtacacttttggccaggggaccaaagtggatagaggtactgactactggggccagggaaccc tcaaac tggtcaccgtctcctcag Omi06gaggtgcagctgttggagtcgggcccagg 701 gccatccggatgacccagtctccatcctccctg 703actggtgaagccttcggagaccctgtccct gctgcatctgtaggagacagagtcaccatctctcacctgcaccgtctctggtggctccatcagc tgccgggcaggtcagagcattagcagctttttacagatactcctggtcctggatccggcagccc attggtatcagcagaaagtagggaaagcccctgccgggaggggactggagtggatcgggc aagctcctgatctatgatgcgtccagtttgcaaagtatgtatagcagtgggggcaccaactata gtggggtcccatcaaggttcagtggcagtggatacccctccctcgagagtcgagtcaccatgtca ctgggacagatttcactctcaccatcagcagtccttgacacgtccaagaagcagttctccctga tgcaacctgaagattttgcagcttactactgtcaagctgagctctgtgaccgccgcggacacg acagagttacgaaaacccgcttactttcggcggccgtgtattactgtgcggcggcttcaattga gagggaccaaagtggatatcaaactcaagtatgggggacttatcgtgatgcttttga tatctggggtcaagggacaatggtcaccgtctcttcag Omi08 gaagtgcagctggtggagtctggggctga 711cagtctgtcgtgacgcagccgccctcagtgtct 713 ggtgaagaggcctggggcctcagtgaagggggccccagggcagagggtcaccatctcct gtttcctgcaaggcatctggatacaccttcacgcactgggagcagctccaacatcggggcaggt caactactttatgcactgggtgcgacaggcctatgatgtacactggtaccagcagcttccagga cctggacaagggcttgagtggatgggagttgcagcccccaaactcctcatctatggtaacac atcaaccctagtgatggtggcgcaagctaccaatcggccctcaggggtccctgaccgattctct ccacagaagttccagggcagagtcaccatggctccaagtctggcacctccgcctccctggc gaccagggacacgtccacgagcacagtctcatcactgggctccaggctgaggatgaggct acatggatctgagcagcctgagatctgagggattattactgccagtcctatgacatcaccctga acacggccgtctattcctgtgcgaggggggtggttcggggtatgtcttcggaactgggaccaa gcttttgatgttagcggcagctggtacgtccggtcaccgtcctag cctttgactactggggccagggaactctgg tcaccgtctcctcag Omi09caggtgcagctggtggagtctgggggag 721 tcctatgagctgacacagccaccctcggtgtc 723gcgtggtccagcctgggaggtccctgag agtgtccccaggacagacggccaggatcaccactctcctgtgcagcctctggattcaccttc tgctctggagatgcattgccaaagcaatatacttaggacctatgctgtgcactgggtccgcca attggtaccagcagaagccaggccagcccccggctccaggcaaggggccagagtgggt tgtgctggtgatatataaagacagtgagaggcggcagttatatcatatgatggaagtaataa cctcagggatccctgagcgattctctggctccaatactacgcagactccgttaagggccgatt gctcagggacaacagtcacgttgaccatcagtcaccctctccagagacacttccaagaaca ggagtccaggcagaagatgaggctgactattacgctgtatctgcaaatgaacagcctgaga ctgtcaatcaacagacagcagtgctacttatccgctgaggacacggctgtgtattactgtgc gggaaatgtggttttcggcggagggaccaagtgagcagaggggacacggtgactacagg tgaccgtcctag tgacgcttttgatatctggggccaagggacaatggtcaccgtctcttcag Omi12 gaggtgcagctggtggagtctgggcctg 731gccatccggatgacccagtctccaggcaccct 733 aggtgaagaagcctgggacctcagtgaaggtctttgtctccaggggaaagagccaccctctc gtctcctgcaaggcgtctggattcagttttactgcagggccagtcagagcgttaggagcagtt gtatgtctgctatgcagtgggtgcgacgggacttagcctggtaccagcagaaacctggccag ctcgtggacaacgccttgagtggataggatgctcccaggctcctcatctatggtgcatccacc ggatcgtccctggcagtggtaacgcaaactagggccactggcatcccagacaggttcagtg acgcgcagaagtttcaggaaagagtcaccgcagtgggtctgggacagacttcattctcacca attactagggacgagtccacaaacacagtcaacagactggagcctgaagatcttgcagtct gttatatggagttgagcagcctgagatccattactgtcagcagtttggtagctcaccatggac gaggacacggccgtgtattattgtgcggcgttcggccaagggaccaaagtggatatcaaac ccctcattgtaataagaccaactgctatgatgcttttgatatctggggccaagggacaat ggtcaccgtctcttcag Omi16gaggtgcagctggtggagtctgggggag 741 gatgttgtgatgactcagtctccaggcaccctgg 743gtgtggtccagcctggggggtccctgaga ctttgtctccaggggaaagagccaccctctcctgcctctcctgtgcagcctctggaatcatagtca aggaccagccagagtgttagcagcaactacttagtgccaactacatgacctgggtccgccagg gcctggtaccagcagaaacctggccaggctccctccagggaaggggctggaatgggtctca caggctcctcatctatggtgcatccagcagggccgttatttatcccggtggtagcacattctacgc actggcatcccagacaggttcagtggcagtgggggactccgtgaagggccgattcaccatctc tctgggacagacttcactctcaccatcagcagaccagagacaactccaagaacacactgtatctt tggagcctgaagattttgcagtgtattactgtcagcaaatgaacagcctgagagttgaggactcg cagtttggtagttcacctcggtacacttttggccagctgtgtattactgtgcgagagatttggagct ggggaccaaggtggagatcaaacggctggtttcaatgacttctggggtcaggga accctggtcaccgtctcctcag Omi17caggtgcagctggtggagtctgggggag 751 gatattgtgatgacccagtctccgggcaccctg 753gtgtggtccagcctggggggtccctgag tctttgtctccaggggaaagagccaccctctccactctcctgtgcagcctctggagtcaccgt tgcagggccagtcagggtgttagcagcatctacagtagcaactacatgagctgggtccgcc cttagcctggtaccagcagaaacctggccaggaggctccagggaaggggctggagtggg ctcccaggctcgtcctctatggcgcatccagtatctcagttctttatgccggtggtagcacatt gggccactggcatcccagacaggttcagtggctacgcagactccgtgaagggccgattca cagtgggtctgggacagacttcactctcaccatccatctccagagacaattccaagaacacgc cagcagactggagcctgaagattttgcagtgttgtatcttcaaatgaacagcctgagagctga attactgtcagcagtatggtagctcacctcggtggacacggctgcgtattactgtgcgagagat acacttttggccaggggaccaaggtggagatcttggcagtggctggtttccttgactcctggg aaac gccagggaaccctggtcaccgtctcctca gOmi18 caggtgcagctggtggagtctggaggag 761 tcctatgagctgactcagccaccctcggtgtca763 gcttgatccagccgggggggtccctgaga gtggccccaggacagacggccaggattacctgctctcctgtgcagcctctgggatcaccgtc tgggggaaacaacgatggagctaaaagtgtgagtagcaactacatgacctgggtccgcca cactggtaccagcagaagccaggccaggccggctccagggaaggggctggagtgggt cctgtgctggtcgtctatgatgatagcgaccggctcacttctttatgccggtggtagcgcattc ccctcagggatccctgaacgattctctggctcctatgctgactccgtgaagggccgattcac aactctgggaacacggccaccctgaccatcacatctccagagacaattccaagaacacgct ccaggatcgaagccggggatgaggccgactgtatcttctaatgaacagcctgagagtcgg attactgtcaggtctgggatagtagtcgtgatcacgacacggccgtttattactgtgcgagag tgtcttcggaactgggaccaaggtcaccgtcctatctccaggtctacggtatggacgtctggg gg gccaagggaccacggtcaccgtctcctc a Omi20gaggtgcagctggtggagtctgggggag 771 gccatccagatgacccagtctccatccttcctg 773gcttggtccagcctggggggtccctgag tctgcatctgtaggagacagagtcaccatcactgctctcctgtgaagcctctgaaataaccgt tgccgggccagtcagggcattagcggtgatttcagtagcaactacatgaattgggtccgcca agcctggtatcag caaaaaccagggaaagccggctccagggaaggggctggagtgggt cctaagctcctgatctatgctgcatccactttgcctcagttctttttgccggtggtactacatact aaagtggggtcccatcaaggttcagcggcagtacgcagactccgtgaagggccgattcac ggatctgggacagaattcactctcacaatcagccatctccagagacaattccaagaacacac agcctgcagcctgaagattttgcaacttattacttgtatcttcaaatgaacaccctgagaattga gtcaacaccttaatagttaccctctcacgttcggggacacggctatttattactgtgcgagaga cggagggaccaaggtggaaatcaaactctcgtcgcatacggtgtggacgtctggg gccaagggaccacggtcaccgtctcctca Omi23caggtacagctgcaggagtcgggcccag 781 gccatccagatgacccagtctccatcctccctg 783gactggtgaagtcttcacagaccctgtccc tctgcatctgtaggagacagagtcaccatcacttcacgtgcactgtctctggtgactccatca tgccgggcgagtcaggccattagcaattctttagccgtggtggttactactggagctggatcc gcctggtatcagcagaaaccagggaaagcccgccagcacccagggaagggcctggagt ctaagctcctactctatgctgcatccacattggaggattgggtccatctattacagtgggagca aagtggggtcccatccaggttcagtggcagtgcctactacaacccgtccctcaagagtcgatt gatctgggacggatttcactctcaccatcagcataccatatcagtagacacgtctaagaacca gcctgcagcctgaagattttgcaacttatttctgtgttctccctgaagctgagctctgtgactgc cagcagtactatagtacccctccgaggacgttcgcggacacggccgtgtatcactgtgcga cggccaagggaccaaagtggatatcaaacgagaaattggtttccttgactactggggcc agggaaccctggtcaccgtctcctcag Omi24caggtgcagctggtggagtctggggctg 791 cgtcattggatgacccagtctccagccaccct 793aggtgaagaagcctgggtcctcggtgaa gtctgtgtctccaggggaaagagccaccctctggtctcctgcaaggcttctggaggcacctt cctgcagggccagtcaaagtattggcagcaacagcagccatggtgtcatctgggtgcgac cttagcctggtaccagcagaaacctggtcaggaggcccctggacaagggcttgagtggat ctcccaggctcctcatctatggtgcagccaccagggagggatcatccccatctttcccacag gggccactggtatcccagccaggttcagtggccaaactacgcacagaaattccagggcag agtgggtctgggacagagttcactctcaccatcagtcacaattaccgcggacaaaccctcca agcagcctgcagtctgaagattttgcagtttactacacagcctacatggagctgagcagcct actgtcagcagtataatgactggcctccgaggagagatctgaggacacggccgtatattact cgttcggccaagggaccaaggtggaaatcaagtgcgagggcaaggggagaacatgattc ac cgtttggggaagttttcattactattttgactactggggccagggaaccctggtcaccgtct cctcag Omi25 caggtgcagctggtggagtctgggggag801 gccatccagatgacccagtctccatcctccctg 803 gcttggtacagcctggcaggtccctgagatctgcatctgtaggagacagagtcaccatcact ctctcctgtgcagcctctggattcacgtttgattgccggacaagtcagaccattagcagctattta gattatgccatgcactgggtccggcaagttaattggtatcagcagaaaccagggaaagccc ccagggaagggcctggagtgggtctcagctaagctcctgatatatgacgcatccagtttgca gaattagttggaacagtggtagcatagtctaagtggggtcccatcaaggttcagtggcagtg atgcggactttgtgaagggccgattcaccgatatgggacagatttcactctcaccatcagca atcgccagagacaacgccaagaactcccgtctgcaacctgaagattttgcaacttacttctgt tgtttctgcaaatgaacagtctgagagctgcaacagagttacaataccccgtacgcttttggc aggacacggccttgtattactgtgcaaaaacaggggaccaaggtggagatcaaac gtacggctctacgtcatcagtactactacggtatggacgtctggggccaagggaccac ggtcaccgtctcctca Omi26caggttcagctggtgcagtctggcactga 811 cagtctgtcgtgacgcagccaccctcggtgtc 813ggtgaagaagcctggggcctcagtgaaggt tgaagcccccaggcagagggtcaccatctccctcctgcaaggcttctgattacacctttacca tgttctggaagcaactccaacatcggaaataaggtttggtatcatctgggtgcgacaggcc tgctgtaaactggtaccagcagctcccaggacctggacaagggcttgagtggatgggac aaggctcccaaactcctcgtctattatgatgatagatcaacccttacaatggtaacacagact ctgctgccctcaggggtctctgaccgattctctatgcacagaagttccagggcagagtcac ggctccaagtctggcacctcagcctccctggcttgaccacagacacatccacgaacaca ccatcagtgggctccagtctgaggataaggcgcctacatggaactgaggagcctgagatc tgattattactgtgcagcatgggatgacagccttgacgacacggccgtgtattattgtgcgag gaatgccttggtgttcggcggagggaccaaggtccgctgggagccctaccggccttgact ctgaccgtcctag actggggccagggaaccctggtcaccgtctcctcag Omi27 gaagtgcagctgttggagtctgggggag 821gaaatagtgatgacgcagtctccatcctccctg 823 gcttggtccagcctggggggtccctgagatctgcatctgtaggagacagagttaccatcactt ctctcctgtgtagcctctggactcaccgtcagccgggcaagtcagggcattggaaatgattta gtagcaactacatgagctgggtccgccaggggtggtatcagcagaaaccagggaaagccc gctccagggaaggggctggagtgggtctctaaagtcctgatttatgctgcatccaatttacaa caattatttatcccggtggtaccacatactaagtggggtcccatcaaggttcagcggcagtg cgcagactccgtgaagggcagattcaccgatctggcacagatttcactctcaccatcagca acctccagagacaaatccaagaacacgctgcctgcagcctgaagattttgcaacttattactg gtatcttcaaatgaacagcctgagagccgtctacaagattccaattatccctacacttttggcc aggacacggctgtgtattactgtgcgagaaggggaccaaggtggagatcaaac gatctggcagtggctgggggtatggacgtctggggccaagggaccacggtcaccgtc tcctca Omi28 gaagtgcagctggtggagtctgggggagg831 gatgttgtgatgactcagtctccaggcaccctg 833 cttggtccagcctggggggtccctgagacttctttgtctccaggggaaagagccaccctctcc ctcctgtgcagcctctggagtcatcgtcagttgcagggccagtcagtttattggcagctcctac agcaactacatgagctgggtccgccaggctttagcctggtaccagcagaaacctggccaggc ccagggaaggggctgcaatgggtctcagtttcccaggctcctcatctatggtgcatccaacag atttatagcggtggtagcactttctacgcagggccactggcgtcccagacaggttcagtggc actccgtgaagggcagattcaccatctccaagtgggtctgggacagacttcactctcaccatc gagacaattccaagaacacgttgtatcttcaagcagactggagcctgaagattttgcagtgtat aatgaacagcctgagagccgaggacacgtactgtcagcagtatgggagtgcacctgggac gctgtgtattactgtgcgagagatttgttagagttcggccaagggaccaaggtggaaatcaaa ggcaggcggaactgactactggggccag cggaaccctggtcaccgtctcctcag Omi29 caggtgcagctggtggagtctggaggagg 841aattttatgctgactcagcctgcctccgtgtctg 843 cttggtccagcctggggggtccctgagactggtctcctggacagtcgatcaccatctcctgca ctcctgtgcagcctctggtttaatcgtcagtactggaaccagcagtgacgttggtggttataact ggaactacatgagctgggtccgccaggctatgtctcctggtaccaacagcacccaggcaaa ccagggaaggggctggagtgggtctcactgcccccaaactcatgatttatgatgtcagtaatc tatttatgccggtggtagcacattctactcagggccctcaggggtttctaatcgcttctctggctc actccgtgaagggccgattcaccatctccacaactctggcaacacggcctccctcaccatct gacacagttccgagaacacgctgtttcttcactgggctccaggctgaggacgaggctgattat aatgaacagcctgagagctgaggacacggtactgcagctcatatacaagcggcagcacttgg ctgtgtattattgtgcgagagatctagtccacgtgttcggcggagggaccaagctgaccgtcc tacggcatggacgtctggggccaagggac tagcacggtcaccgtctcctca Omi30 gaagtgcagctggtggagtctggggctg 851cagtctgtgctgactcagccaccctcagcgtct 853 aggtgaagaagcctgggtcctcagtgaagggacccccgggcagagggtcaccatctctt ggtctcctgcaaggcttctggaggcaccttgttctggaagcagctccaacatcggaggcgat cagcaggtatgctatcagctgggtgcgacattgtaaactggtacctccagctcccagggacg aggcccctggacaaggacttgagtggatgcccccaaactcctcatttatagtaataatcagc gggagggatcatccctatctttgatgcaacggccctcaggcgtccctgaccgattctctggc aaactacgcacagaagttccatgacagagtccaggtctggcacctcagcctccctggccat tcaccattaccgcggacaaatccgcgagccagtgggctccagtctgaggatgagggttatt acagcctacatggaactgagcagcctgaattactgtgcagcatgggatgacagcctgaatg gatctgacgacacggccgtgtattactgtggtcaagtgttcggcggagggaccaagctgac cgagagaacggacatattgtagtggtggt cgtcctagacttgctacggaggatacttctactacggt atggacgtctggggccaaggaaccacggtcaccgtctcctca Omi31 gaggtgcagctggtgcagtctggggctg 861cagtctgtcgtgacgcagccaccctcagcgtct 863 aggtgaagaagcctgggtcctcggtgaagggacccccgggcagagggtcaccatctcttgt ggtctcctgcaaggcttctggaggcacctttctggaagcagctccgacatcggaagtaatactgt cagtagctatggtatcagctgggtgcgacaaactggtaccagcagctcccaggaacggccc aggcccctggactagggcttgagtggatgccaaactcctcatctatactaataatcagcggcc gggggggtcatccctatcctaagtgcaaactcaggggtccctgaccgattctctggctccaag acactacgcgcagcggttccagggcagatctggcacctcagcctccctggccatcactgggct gtcacgatcaccgcggacaagtccacggccagtctgaggatgaggctgattatttctgtgcag gcacagcctacatggagctgagcagcctcatgggatgaaagcctgaatggtcgagtgttcgg gagatctgaggacacggccgtatactactcggagggaccaagctgaccgtcctag gtgcgagagatatccttcatcatgacgacctttgggggaggttctactacgacggtatgg acgtctggggccaagggaccacggtcac cgtctcctcaOmi32 gaagtgcaactggtggagtctgggggag 871 gccatccggatgacccagtctccaggcaccct873 gcgtggtccagcctgggaggtccctgag gtctttgtctccaggggaaagagccaccctctcactctcctgtgcagcgtctggattcaccttc ctgcagggccagtcagagtattagtagcagctagtaactatggcatgcactgggtccgcca tcttagcctggtaccagcagaaacctggccagggctccaggcaagggactggagtgggtg gctcccaggctcctcatctatggtgcatccagcgcagtttattggtatgatggaggtaataaat agggccactggcatcccagacaggttcagtgtctatgcagactccgtgaagggccgattc gcagtgggtctgggacagacttcactctcaccaccatctccagagacaattccaagaatac atcagcagactggagcctgaagattttgcagtgttgtatctgcaaatgaacagcctgagagt gtattactgtcagcagtatggtacctcaccaagcgaggacacggctgtttattactgtgcgag gctcactttcggcggagggaccaaagtggataagatacggctcctccggactactggggcc tcaaac agggaaccctggtcaccgtctcctcag Omi33gaggtgcagctgttggagtctgggggag 881 gaaattgtgttgacgcagtctccaggcaccct 883gcgtggtccagcctggaaggtccctgag gtctttgtctccaggggaaagagccaccctctcactctcctgtgcagcgtctggattcaaattc ctgcagggccagtcagagtattagtagcaacttagtgactatggcatgcactgggtccgcca cttagcctggtaccagcagaaacctggccaggggctccaggcaaggggctggagtgggt ctcccaggctcctcatctatggtgcatccagcaggcagtttattggtatgatggaggtactaa gggccactggcatcccagacaggttcagtggattctatgcagactccgtgaagggccgatt cagtgggtctgggacagacttcactctcaccatcaccatctccagagacaattccaagaata cagcagactggagcctgaagattttgcagtgtcgttgtatctgcaaatgagcagcctgaga attactgtcagcagtatggtacctcaccaaggcgtcgaggacacggctgtttattactgtgcg tcactttcggcggagggaccaaagtggatatcagagatacggctcctccggactactggg aaac gccagggaaccctggtcaccgtctcctca g Omi34caggttcagctggtgcagtctggggctgag 891 cagtctgtgttgacgcagccgccctcagtgtct 893gtgaagaagcctgggtcctcggtgaaggt ggggccccggggcagagggtcaccatctcctctcctgcaaggcttctggaggcaccttcag gcactgggagcagctccaacatcggggcagacagttatggtatcaggtgggtgcgacaggc ttatgatgtacactggtaccagcaacttccaggccctggacaagggcttgagtggatgggag agcagcccccaaactcctcatctatggtaacaaggatcatccccgtgtttggtgcaacaaacta caaccggccctcaggggtccctgaccgattctcgcacagaagttccaggacagagtcacaa ccggctccaagtctggcacctcagcctccctgttaccgcggacaaatccacggccacagcct gccatcactgggctccaggctgaggatgaggacatggaattgagtagcctgaaatctgacg ctgattattactgccagtcctatgacagcagccacacggccgtgtatttttgtgcgagagatgc agaatgctttctatgtcttcggaactgggaccaaccttagtgccagtggctggacgggcccctt ggtcaccgtcctagtgactcgtggggccagggaaccctggtca ccgtctcctca Omi35caggtgcagctggtggagtctgggggagg 901 cagtctgtggtgactcagccaccctcggtgtca 903cttggtacagcctggcaggtccctgagact gtggccccaggacagacggccaggattacctgctcctgtgcagcctctggattcacctttgatg tggaggaaccaacattggaagtaaaagtgtccattatgccatgcactgggtccggcaagctc actggtaccagcagaagccaggccaggccccagggaagggcctggagtgggtctcagg ctgtgctggtcgtctatgatgatagcgaccggcaagtacttggaatagtggtaccatagactat cctcagggatccctgagcgattctctggctccagcggactctgtgaagggccgattcaccatc actctgggaacacggccaccctgaccatcactccagagacaacgccaagaactccctgtat ctgggtcgaagccggggatgaggccgactatctgcaaatgaacagtctgagagctgaggac tactgtcaggtgtgggatagtagtagtgataatacggccttgtattactgtgcaaaagataggt gtgctattcggcggagggaccaagctgaccgttcgtaaaggttgtagtagtaccggctgctat tcctag aaggagaactacggtatggacgtctggggccaagggaccacggtcaccgtctcctca Omi36 gaggtgcagctggtggagtctgggggag 911gatattgtgatgactcagtctccaggcaccctg 1913 gtgtggtccagcctggggggtccctgagtctttgtctccaggggaaagagccaccctctcc actctcctgtgcagcctctggaatcatagtctgcaggaccagtcagagtgttagcagcaacta agtgccaactacatgacctgggtccgccacttagcctggtaccagcagaaacctggccagg ggctccagggaagggactggaatgggtcctcccaggctcctcatctatggtgcatccagca tcagttatttaccccggtggtagcacattctgggccactggcatcccagacaggttcagtgg acgcggactccgtgaagggccgattcaccagtgggtctgggacagacttcactctcaccat catctccagagacaactccaagaacacgtcagcagactggagcctgaagattttgcagtgt tgtatcttcaaatgaacagcctgagagttgattactgtcagcagtttggtagttcacctcggta aggactcggctgtgtattactgtgcgagacacttttggccaggggaccaaggtggagatca gatttggagctggctggtttcaatgactact aacggggccagggaaccctggtcaccgtctc ctcag Omi38 caggtgcagctggtggagtctggggctga921 gccatccggatgacccagtctccttccaccctg 923 ggtgaagaagcctgggtcctcggtgaaggtctgcatctgtaggagacagagtcaccatcact tctcctgcaaggcttctggaggaaacttcaatgccgggccagtcagactattaatagttggttg catgtatactatcagttgggtgcgacaggccgcctggtatcagcagaaacccgggaaagcccc cctggacgaggacttgagtggatgggaagtaagctcctgatctatgatgcctccaatttggaa gttcatccctatcgctaataaagcaaactacagtggggtcccatcaaggttcagcggcagtg gcacagaactttccgggcagagtcaccattgatctgggacagaattcactctcaccatcagca accgcggacaaatccactagcacagtctacgcctgcagcctgatgattttgcaacttattactgc atggagctgagaagcctgacatctgacgaccaacagtatgaaagttattctccgatcaccttcg acggccgtgtattactgtgcgagaagtggggccaagggacacgactggagattaaac agctacgatgcttttgatgtgtggggccaagggacaatggtcaccgtctcttcag Omi39 caggtgcagctggtggagtctgggggag 931gaaattgtgttgacacagtctccagactccctg 933 tcgtggtacagcctggggggtccctgagagctgtgtctctgggcgagagggccaccatca ctctcctgtgcagcctctggattcagctttgactgcaagtccagccagaatgttttatacagctc atgattatagcatgcactgggtccgtcaagcaacaataagaattacttagcttggtaccagcag ctccggggaagggtctggagtgggtctctaaaccaggacagcctcctcaactactcatttac gtcatttactgggatggtgttagcaaatacttgggcatctacccgggaatccggggtccctg atgcagactctgtgaagggccgattcaccaccgattcagtggcagcgggtctgggacaga atctccagagacaacagcaaaaactcccttttcactctcaccatcagcagcctgcaggctga gtatttgcaaatgaacagtctgagaactgaagatgtggcagtttattactgtcaccaatattata ggacaccgccgtatattactgtgcaaaaggtactccattcactttcggccctgggaccaaag atagtgaggattgtagtagtaccagctgcttggatatcaaac acatggacgtctggggcaaagggaccac ggtcaccgtctcctca Omi41caggttcagctggtgcagtctggagctga 941 gccatccagatgacccagtctccagactccct 943ggtgaagaagcctggggcctcagtgaagg ggctgtgtctctgggcgagagggccaccatctctcctgcaaggctgctggttacagctttat aactgcaagtccagccagagtgttttatacagcgaactacggtatcaactgggtgcgacag tccaacaataagaattacttagcttggtaccaggcccctggacaagggcttgagtggatgg cagaaaccaggacagcctcctaagctggtcattgatggatcaacacttacaatggtaacgca tactgggcatctacccgggaatccggggtccctaagtatgcacagaagttccagggccgagt gaccgattcagtggcagcgggtctgggacagacaccatgaccacagacacatccacgagc tttcactctcaccatcagcagcctgcaggctgaacagcctacatggagctgaggagcctga agatgtggcagtttattactgtcaccaatattatagatcgggcgacacggccgtgtattactgt gtagtcctcgcacttttggccaggggaccaaggtgcgagggaccctttcaccggttatgatga ggaaatcaaac cgtttgggggggggactactggggccagggaaccctggtcaccgtctcctcag Omi42 gaggtgcagctgttggagactgggggag 951cagtctgtcgtgacgcagcctccctccgcgtc 952 gcttggttcagcccggcaggtccctgagaggggtctcttggacagtcagtcaccatctcctg ctctcctgtgcagcctcgggattcccctttgcactggaaccagcagtgacgttggtggttaca atgattatgccatccactgggtccggctagactatgtctcttggtaccaacaacacccaggc ctccagggaagggcctggagtgggtctcaaagcccccaaactcatgatttttgaggtcagt aagtattagttgggatagtggtagcataggaagcggccctcaggggtccctgatcgcttctc ctatgcggactctgtgaagggccggttcatggctccaagtctggcaacacggcctccctga ccatctccagagacaacgccaagaactcccgtctctgggctccaggctgaggatgaggc cctgtatctgcaaatgaacagtctgagagtgattattactgcagctcatatgcaggcaacaaa ctgaggacacggccttgtattactgtgcaaggggtcttcggcggagggaccaaattgaccgtc agggggcctttcccgggtatagcagtgg ctcgctggtactacggtttggacgtctggggcc aaggggccacggtcaccgtctcctca

Amino Acid Sequence of CDRs

Heavy Chain CDR SEQ SEQ SEQ Antibody ID ID ID number: CDR1-IMGT NO.CDR2-IMGT NO. CDR3-IMGT NO. Omi02 GGTFSSYA 685 IIPIFRTP 686ASPSCGGDCPQYL 687 KSSKLDWYFDL Omi03 EIIVSRNY 695 IYSGGST 696ARDLDVVGGTDY 697 Omi06 GGSISRYS 705 MYSSGGT 706 AAASIDQVWGTYR 707 DAFDIOmi08 GYTFTNYF 715 INPSDGGA 716 ARGAFDVSGSWYV 717 PFDY Omi09 GFTFRTYA725 ISYDGSNK 726 ASRGDTVTTGDAF 727 DI Omi12 GFSFSMSA 735 IVPGSGNA 736AAPHCNKTNCYDA 737 FDI Omi16 GIIVSANY 745 IYPGGST 746 ARDLELAGFNDF 747Omi17 GVTVSSNY 755 LYAGGST 756 ARDLAVAGFLDS 757 Omi18 GITVSSNY 765LYAGGSA 766 ARDLQVYGMDV 767 Omi20 EITVSSNY 775 LFAGGTT 776 ARDLVAYGVDV777 Omi23 GDSISRGG 785 IYYSGST 786 AREIGFLDY 787 YY Omi24 GGTFSSHG 795IIPIFPTA 796 ARARGEHDSVWGS 797 FHYYFDY Omi25 GFTFDDYA 805 ISWNSGSI 806AKSTALRHQYYYG 807 MDV Omi26 DYTFTRFG 815 INPYNGNT 816 ARSAGSPTGLDY 817Omi27 GLTVSSNY 825 IYPGGTT 826 ARDLAVAGGMDV 827 Omi28 GVIVSSNY 835IYSGGST 836 ARDLLEAGGTDY 837 Omi29 GLIVSRNY 845 IYAGGST 846 ARDLVHYGMDV847 Omi30 GGTFSRYA 855 IIPIFDAT 856 ARERTYCSGGTCY 857 GGYFYYGMDV Omi31GGTFSSYG 865 VIPILSAK 866 ARDILHHDDLWGR 867 FYYDGMDV Omi32 GFTFSNYG 875YWYDGGN 876 ARDTAPPDY 877 K Omi33 GFKFSDYG 885 YWYDGGT 886 ARDTAPPDY 887K Omi34 GGTFSSYG 895 IIPVFGAT 896 ARDALSASGWTGP 897 FDS Omi35 GFTFDDYA905 STWNSGTI 906 AKDRFRKGCSSTG 907 CYKENYGMDV Omi36 GIIVSANY 915 IYPGGST916 ARDLELAGENDY 917 Omi38 GGNFNMY 925 FIPIANKA 926 ARSGSYDAFDV 927 TOmi39 GFSFDDYS 935 TYWDGVSK 936 AKDSEDCSSTSCY 937 MDV Omi41 GYSFMNY 945INTYNGNA 946 ARDPFTGYDDVWG 947 G GDY Omi42 GFPFDDYA 955 ISWDSGSI 956AKGAFPGYSSGWY 957 YGLDV

Light Chain CDR SEQ SEQ SEQ Antibody ID ID ID number: CDR1-IMGT NO.CDR2-IMGT NO. CDR3-IMGT NO. Omi02 QSVSSTY 688 GAS 689 QHYGSSPLT 690Omi03 QSVSSSY 698 GAS 699 QQYGSSPGYT 700 Omi06 QSISSF 708 DAS 709QQSYENPLT 710 Omi08 SSNIGAGYD 718 GNT 719 QSYDITLSGSGYV 720 Omi09 ALPKQY728 KDS 729 QSTDSSATYPGNVV 730 Omi12 QSVRSSY 738 GAS 739 QQFGSSPWT 740Omi16 QSVSSNY 748 GAS 749 QQFGSSPRYT 750 Omi17 QGVSSIY 758 GAS 759QQYGSSPRYT 760 Omi18 NDGAKS 768 DDS 769 QVWDSSRDHV 770 Omi20 QGISGD 778AAS 779 QHLNSYPLT 780 Omi23 QAISNS 788 AAS 789 QQYYSTPPRT 790 Omi24QSIGSN 798 GAA 799 QQYNDWPPRT 800 Omi25 QTISSY 808 DAS 809 QQSYNTPYA 810Omi26 NSNIGNNA 818 YDD 819 AAWDDSLNALV 820 Omi27 QGIGND 828 AAS 829LQDSNYPYT 830 Omi28 QFIGSSY 838 GAS 839 QQYGSAPGT 840 Omi29 SSDVGGYNY848 DVS 849 SSYTSGSTWV 850 Omi30 SSNIGGDI 858 SNN 859 AAWDDSLNGQV 860Omi31 SSDIGSNT 868 TNN 869 AAWDESLNGRV 870 Omi32 QSISSSF 878 GAS 879QQYGTSPRLT 880 Omi33 QSISSNF 888 GAS 889 QQYGTSPRLT 890 Omi34 SSNIGADYD898 GNN 899 QSYDSSQNAFYV 900 Omi35 NIGSKS 908 DDS 909 QVWDSSSDNVL 910Omi36 QSVSSNY 918 GAS 919 QQFGSSPRYT 920 Omi38 QTINSW 928 DAS 929QQYESYSPIT 930 Omi39 QNVLYSSNNKNY 938 WAS 939 HQYYSTPFT 940 Omi41QSVLYSSNNKNY 948 WAS 949 HQYYSSPRT 950 Omi42 SSDVGGYNY 958 EVS 959SSYAGNKGV 960

-amino acid sequence encoded by IGHV1-58 germline V-gene sequenceSEQ ID NO: 961 MQLVQSGPEVKKPGTSVKVSCKASGFTFTSSAVQWVRQARGQRLEWIGWIVVGSGNTNYAQKFQERVTITRDMSTSTAYMELSSLRSEDTAVYYCAA-AZD8895 (COV2-2196) heavy chain variable region nucleotide sequenceGenbank: MT763531.1 SEQ ID NO: 962CAAATGCAGCTGGTGCAGTCTGGGCCTGAGGTGAAGAAGCCTGGGACCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTCACCTTTATGAGCTCTGCTGTGCAGTGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGATGGATCGTCATTGGCAGTGGTAACACAAACTACGCACAGAAGTTCCAGGAAAGAGTCACCATTACCAGGGACATGTCCACAAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACGGCCGTGTATTACTGTGCGGCCCCATATTGTAGTAGTATCAGCTGCAATGATGGTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA-AZD8895 (COV2-2196) heavy chain variable region amino acid sequence:GenBank: QLI33947.1 SEQ ID NO: 963QMQLVQSGPEVKKPGTSVKVSCKASGFTFMSSAVQWVRQARGQRLEWIGWIVIGSGNTNYAQKFQERVTITRDMSTSTAYMELSSLRSEDTAVYYCAAPYCSSISCNDGF DIWGQGTMVTVSS-AZD8895 (COV2-2196) light chain variable region nucleotide Sequence:GenBank: MT763532.1 SEQ ID NO: 964GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAGAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCACTATGGTAGCTCACGGGGTTGGACGTTCGGCCAAGGGACCAAGGTG GAAATCAAA-AZD8895 (COV2-2196) light chain variable domain amino acid sequence:GenBank: QLI33948.1 SEQ ID NO: 965EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSRGWTFGQGTKVEIK-Spike Glycoprotein amino acid sequence of WIV04 isolateGenbank Ref. QHR63260.2 SEQ ID NO: 966MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT-amino acid sequence encoded by germline IGLV Kappa 3-20 SEQ ID NO: 967EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSP

1. An antibody capable of binding to the spike protein of coronavirusSARS-CoV-2, wherein the antibody comprises at least three CDRs ofantibody Omi12, or of any one of the 27 antibodies in Table
 3. 2. Theantibody according to claim 1, comprising: (a) at least four, five, orall six CDRs of an antibody in Table 3; (b) a heavy chain variabledomain comprising or consisting of an amino acid sequence having atleast 80% sequence identity to the heavy chain variable domain of anantibody in Table 3; (c) a light chain variable domain comprising orconsisting of an amino acid sequence having at least 80% sequenceidentity to the light chain variable domain of an antibody in Table 3;and/or (d) a heavy chain variable domain and a light chain variabledomain comprising or consisting of an amino acid sequence having atleast 80% identity to the heavy chain variable domain and light chaindomain, respectively, of an antibody in Table
 3. 3. The antibody ofclaim 1 or claim 2, wherein the antibody in Table 3 is selected from thegroup consisting of: (a) Omi02, Omi03, Omi12, Omi18, Omi28, Omi39 andOmi42; (b) Omi03 and Omi12; (c) Omi03, Omi12, Omi02, Omi39, and Omi42;(d) Omi03, Omi12, Omi02, Omi39, Omi42, Omi16, Omi18, Omi20, Omi 23,Omi28 and Omi08; or (e) Omi03, Omi12, Omi02, Omi39, Omi42, Omi16, Omi18,Omi20, Omi 23, Omi28, Omi08, Omi17, Omi29, Omi36 and Omi38.
 4. Theantibody according to claim 1, comprising CDRH1, CDRH2 and CDRH3, from afirst antibody in any one of Tables 1 to 3, and CDRL1, CDRL2 and CDRL3from a second antibody in any one of Tables 1 to 3, with the provisothat the first antibody and the second antibody are different.
 5. Theantibody according to claim 4, comprising a heavy chain variable domainamino acid sequence having at least 80% sequence identity to the heavychain variable domain from a first antibody in any one of Tables 1 to 3,and a light chain variable domain amino acid sequence having at least80% sequence identity to the light chain variable domain from a secondantibody in any one of Tables 1 to
 3. 6. The antibody according to claim4 or claim 5, wherein the first and second antibodies derive from thesame germline heavy chain v-region, optionally wherein the heavy chainv-region is IGHV1-69, IGHV3-53, IGHV1-58, IGHV3-66, IGHV3-30, IGHV3-33,IGHV1-18, IGHV3-9, or IGHV4-31.
 7. The antibody according to any one ofclaims 4 to 6, wherein the first antibody and the second antibody areboth selected from the group consisting of: (a) Omi03, Omi18, Omi29,Beta-27, antibody 150, antibody 158, antibody 175, antibody 222 andantibody 269; optionally wherein the antibody comprises heavy chainvariable domain and light chain variable domain of one of the antibodiesas set out in Table 4; (b) Omi03, Omi18, Omi29, Omi16, Omi17, Omi20,Omi27, Omi36, Beta-27, antibody 150, antibody 158, antibody 175,antibody 222, antibody 269, antibody 40 and antibody 398; optionallywherein the antibody comprises heavy chain variable domain and lightchain variable domain of one of the antibodies as set out in Table 5;(c) Omi12, Beta-47, Beta-25, antibody 55, antibody 165, antibody 253 andantibody 318; optionally wherein the antibody comprises heavy chainvariable domain and light chain variable domain of one of the antibodiesas set out in Table 6; (d) Beta-49, Beta-50, Omi02, Omi24, Omi30, Omi31,Omi34 and Omi38; optionally wherein the antibody comprises heavy chainvariable domain and light chain variable domain of one of the antibodiesas set out in Table 7; (e) Beta-22, Beta-29, antibody 159 and Omi09;optionally wherein the antibody comprises heavy chain variable domainand light chain variable domain of one of the antibodies as set out inTable 8; (f) Beta-20, Beta-43, Omi32 and Omi33; optionally wherein theantibody comprises heavy chain variable domain and light chain variabledomain of one of the antibodies as set out in Table 9; (g) antibody 278,Beta-44, Omi26 and Omi41; optionally wherein the antibody comprisesheavy chain variable domain and light chain variable domain of one ofthe antibodies as set out in Table 10; (h) antibody 58, Omi25, Omi35 andOmi42; optionally wherein the antibody comprises heavy chain variabledomain and light chain variable domain of one of the antibodies as setout in Table 11; or (i) Beta-56 and Omi23; optionally wherein theantibody comprises heavy chain variable domain and light chain variabledomain of one of the antibodies as set out in Table
 12. 8. The antibodyof any one of the preceding claims, wherein the antibody in Tables 3 to12 is selected from the group consisting of: (a) Omi02, Omi03, Omi12,Omi18, Omi28, Omi39 and Omi42; (b) Omi03 and Omi12; (c) Omi03, Omi12,Omi02, Omi39, and Omi42; (d) Omi03, Omi12, Omi02, Omi39, Omi42, Omi16,Omi18, Omi20, Omi 23, Omi28 and Omi08; or (e) Omi03, Omi12, Omi02,Omi39, Omi42, Omi16, Omi18, Omi20, Omi 23, Omi28, Omi08, Omi17, Omi29,Omi36 and Omi38.
 9. The antibody according to any one of the precedingclaims, which is a full-length antibody, e.g. comprising a IgG1 constantregion, or comprises an Fc region comprising at least one modificationsuch that serum half-life is extended.
 10. The antibody according to anyone of the preceding claims, wherein the antibody is derived fromgermline heavy chain IGHV1-58, such as Omi-12, Beta-47, Beta-25,antibody 55, antibody 165, antibody 253, and antibody 318, and comprisesproline at position 53 in the heavy chain variable region.
 11. Acombination of antibodies comprising two or more antibodies according toany one of the preceding claims.
 12. A combination of antibodiescomprising: (a) the antibody according to any one of claims 1 to 10; and(b) an antibody comprising at least three CDRs of an antibody in Table 1or Table 2, for example, the antibody comprises: (i) at least four,five, or all six CDRs of an antibody in Table 1 or Table 2; (ii) a heavychain variable domain comprising or consist of an amino acid sequencehaving at least 80% sequence identity to the heavy chain variable domainof an antibody in Table 1 or Table 2; (iii) a light chain variabledomain comprising or consist of an amino acid sequence having at least80% sequence identity to the light chain variable domain of an antibodyin Table 1 or Table 2; and/or (iv) a heavy chain variable domain and alight chain variable domain comprising or consist of an amino acidsequence having at least 80% identity to the heavy chain variable domainand light chain domain, respectively, of an antibody in Table 1 or Table2.
 13. The combination of antibodies according to claim 11 or claim 12,comprising two, three or four antibodies according to any one of claims1 to
 10. 14. One or more polynucleotides encoding the antibody accordingto any one of claims 1 to 10, one or more vectors comprising saidpolynucleotides, or a host cell comprising said vectors.
 15. A methodfor producing an antibody that is capable of binding to the spikeprotein of coronavirus SARS-CoV-2, comprising culturing the host cell ofclaim 14 and isolating the antibody from said culture.
 16. Apharmaceutical composition comprising: (a) the antibody according to anyone of claims 1 to 12, or the combination of antibodies according to anyone of claims 11 to 13, and (b) at least one pharmaceutically acceptablediluent or carrier.
 17. The antibody according to any one of claims 1 to10, the combination according to any one of claims 11 to 13, or thepharmaceutical composition according to claim 16, for use in a methodfor treatment of the human or animal body by therapy.
 18. The antibodyaccording to any one of claims 1 to 10, the combination according to anyone of claims 11 to 13, or the pharmaceutical composition according toclaim 16, for use in a method of treating or preventing coronavirusinfection, or a disease or complication associated with coronavirusinfection.
 19. A method of treating or preventing coronavirus infection,or a disease or complication associated with coronavirus infection in asubject, comprising administering a therapeutically effective amount ofthe antibody according to any one of claims 1 to 10, the combinationaccording to any one of claims 11 to 13, or the pharmaceuticalcomposition according to claim 16, to said subject.
 20. The methodaccording to claim 19 or 20, wherein the method is for treatingSARS-CoV-2 infection, or a disease or complication associated therewith,such as COVID-19.
 21. A method of identifying the presence ofcoronavirus, or a protein fragment thereof, in a sample, comprising: (i)contacting the sample with the antibody according to any one of claims 1to 10, or the combination according to any one of claims 11 to 13, and(ii) detecting the presence or absence of an antibody-antigen complex,wherein the presence of the antibody-antigen complex indicates thepresence of coronavirus, or a fragment thereof, in the sample.
 22. Amethod of treating or preventing coronavirus infection, or a disease orcomplication associated therewith, in a subject, comprising identifyingthe presence of coronavirus according to the method of claim 21 in asample, and treating the subject with the antibody or combinationaccording to any one of claims 1 to 13, an anti-viral drug or ananti-inflammatory agent.
 23. Use of the antibody according to any one ofclaims 1 to 10, the combination according to any one of claims 11 to 13,or the pharmaceutical composition according to claim 16, for preventing,treating and/or diagnosing coronavirus infection, or a disease orcomplication associated therewith.
 24. Use of the antibody according toany one of claims 1 to 10, the combination according to any one ofclaims 11 to 13, or the pharmaceutical composition according to claim16, for the manufacture of a medicament for treating or preventingcoronavirus infection, or a disease or complication associatedtherewith.
 25. The antibody for use according to claim 17 or 18, themethod according to any one of claims 19 to 22 and the use according toclaim 23 or 24, wherein the coronavirus infection is caused by aSARS-CoV-2 strain of the lineage alpha, beta, gamma, delta or omicron,optionally wherein the lineage of the omicron strain is omicron BA.1,omicron BA1.1, omicron BA.2 or omicron BA.3.
 26. An antibody derivedfrom germline heavy chain IGHV1-58, capable of binding to the spikeprotein of coronavirus SARS-CoV-2, wherein the amino acid at position 58in the heavy chain variable region according to IMGT numbering isproline or is substituted with proline.
 27. The antibody of claim 26,wherein the antibody derived from germline heavy chain IGHV1-58 isAZD8895, Omi-12, Beta-47, Beta-25, antibody 55, antibody 165, antibody253, or antibody
 318. 28. An antibody capable of binding to the spikeprotein of coronavirus SARS-CoV-2 comprising a heavy chain variabledomain comprising an amino acid sequence having ≥60%, ≥70%, ≥80%, ≥90%,≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity to SEQ ID NO:961, with the proviso that the amino acid at position 58 according toIMGT numbering is proline or is substituted with proline.
 29. Theantibody of any one of claims 26 to 28, wherein the antibody comprises aheavy chain variable domain comprising an amino acid sequence having≥80%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, ≥99% or 100% sequence identity toSEQ ID NO: 731, 591, 461, 62, 182, 262, 332 or 963, with the provisothat the amino acid at position 58 according to IMGT numbering isproline or is substituted with proline.
 30. The antibody of any one ofclaims 26 to 29, wherein the antibody comprises a heavy chain variabledomain comprising an amino acid sequence having SEQ ID NO: 591, 461, 62,182, 262, or 332, wherein the valine at position 58 according to IMGTnumbering is substituted with a proline.
 31. The antibody of any one ofclaims 26 to 29, wherein the antibody comprises a heavy chain variabledomain comprising an amino acid sequence having SEQ ID NO: 961, whereinthe isoleucine at position 58 according to IMGT numbering is substitutedwith a proline.